Gamma-diketones for treatment and prevention of aging skin and wrinkles

ABSTRACT

The present disclosure relates to γ-diketone compounds, such as those having the structures:The disclosure also relates to cosmetic or dermopharmaceutical compositions comprising the same, and methods for using the compounds or compositions for improving the aesthetic appearance of a subject&#39;s skin, for example, improving one or more of skin tone, radiance, clarity, tautness, skin firmness, plumpness, suppleness, softness, skin texture, skin texturization and moisturization, appearance of skin contours, appearance of hollow cheeks, appearance of sunken, baggy, or dark circles under eyes, skin luster, brightness, skin thickness, and skin elasticity and/or resiliency comprising application of the compounds or compositions disclosed.

RELATED APPLICATIONS

This is a continuation application of U.S. application Ser. No.16/534,455, filed on Aug. 7, 2019, which is a continuation applicationof U.S. application Ser. No. 15/706,908, now U.S. Pat. No. 10,434,052,filed on Sep. 18, 2017, which is a divisional application of U.S.application Ser. No. 14/831,456, now U.S. Pat. No. 9,795,550, filed Aug.20, 2015, which claims the benefit of U.S. Provisional Application No.62/039,786, filed Aug. 20, 2014, each of which are incorporated hereinby reference in their entireties.

BACKGROUND Technical Field

The present disclosure relates to compounds, cosmetic ordermopharmaceutical compositions comprising the same, and methods forusing the compounds or compositions for treating, protecting, and/orimproving the condition and/or aesthetic appearance of skin, forexample, treating, preventing, ameliorating, reducing and/or eliminatingfine lines and/or wrinkles of skin, or improving the appearance of finelines and/or wrinkles of skin, the methods comprising application of thedisclosed compounds or compositions.

Background

Mammalian epidermis and its appendages (e.g., hair, nail, sebaceous andsweat glands) provide a barrier to keep harmful elements out of the bodyand essential body fluids in. As the first line of defense against thevarious physical traumas of the environment, the epidermis must protectitself as well as the underlying tissues. The epidermis is also exposedto mutagenic ultraviolet radiation. In nonhaired or sparsely hairedregions such as most human skin, the epidermis is thicker than that offurred skin, and in these locations the skin functions primarily in aprotective role. The constant assaults on the epidermis necessitateself-renewal, making the epidermis a prime example of an adult tissuethat undergoes continual and rapid flux.

Aged skin differs from youthful skin both in appearance and in function.The aged epidermis lacks keratinocytes and is physically thinner, butmostly from effacement of the rete ridges. In addition to thinning,aging slows wound healing, prolongs epidermal turnover, and impairsbarrier formation. The skin appears thin, wrinkled, bruised, and rough.Wrinkling and bruising can also result from aging-related changes in thedermis. The dermis, too, is characteristically thinner in aged persons.Aged fibroblasts are less likely to synthesize normal amounts ofcollagen, elastin, laminin glycosaminoglycans, and fibronectin. Thedermis can, in such cases, lack elasticity, strength, vessel support,remodeling abilities, and ground substances. For example, rete ridgescan be effaced, and basal cells can no longer display villousprojections into the dermis. Epidermal cell turnover is reduced up to50% in the aged as compared to youth. For example, melanocyte numberscan decrease 8-20% per decade. There are fewer Langerhans cells in theaged, and those present are often functionally impaired. Collagensynthesis decreases, for example, up to 30% within 4 years of menopausein women. The numbers of collagen and elastic fibers are also decreased.The dermis can also become less echogenic to ultrasounds, consistentwith changes in collagen and elastic tissues.

SUMMARY

The present disclosure relates to compounds, compositions comprising thesame, and methods of using the compounds or compositions for treating,protecting, and/or altering (e.g., improving) the condition and/oraesthetic appearance of skin, including, for example, treating,preventing, ameliorating, reducing and/or eliminating fine lines and/orwrinkles of skin and/or improving the aesthetic appearance of fine linesand/or wrinkles of skin, caused by, for example, cellular senescence,environmental damage or dermatoheliosis. The disclosure also relates tomethods for stimulating skin cell renewal, promoting fibroblastproliferation, and/or synthesizing elastin, collagen, proteoglycans, ornew connective tissue, thereby reducing wrinkles, restoring elasticity,resiliency, and/or suppleness to the skin.

Compounds and compositions described herein can be employed for cosmeticuses, dermopharmaceutical uses, or both cosmetic and dermopharmaceuticaluses. A “cosmetic”, as used herein, can be contacted with the skin, suchas by being rubbed, poured, sprinkled, or sprayed on the skin orotherwise introduced into or onto the skin, and is intended to improvethe aesthetic appearance of the skin, such as by cleansing, beautifying,promoting attractiveness, or altering, e.g., improving, the aestheticappearance of the contacted skin. A cosmetic benefit is typically visualor aesthetic, and can be evaluated using subjective or objective assays.

A “dermopharmaceutical” as used herein, can similarly be contacted withthe skin, and is intended to be used in the treatment, mitigation orprevention of a disease or disorder of the skin, and/or is intended toaffect the structure or a function of the skin. A dermopharmaceuticaltypically has a physiological, pharmacological, and/or therapeuticeffect on the skin. A dermopharmaceutical can result in an improvedaesthetic appearance of the skin by virtue of its physiological,pharmacological, or therapeutic effects. A dermopharmaceutical benefitcan be evaluated using subjective or objective assays.

In one embodiment, the present disclosure provides a cosmetic ordermopharmaceutical composition for improving the condition and/oraesthetic appearance of skin, wherein the composition comprises acompound according to Formula I, II, IIIa, IIIb, and/or IV.

In one embodiment, the present disclosure provides a cosmetic ordermopharmaceutical composition for altering the aesthetic appearance ofskin associated with or affected by, or for preventing or reducing,wrinkles, dry skin, sensitive skin, or dermatological symptoms caused byineffective homeostatic regulation of healthy skin, wherein thecomposition comprises a compound according to Formula I, II, IIIa, IIIb,and/or IV.

In one embodiment, the present disclosure provides a cosmetic ordermopharmaceutical composition for altering the aesthetic appearance ofskin associated with or affected by wrinkling, sagging, and/or loss ofskin elasticity, wherein the composition comprises a compound accordingto Formula I, II, IIIa, IIIb, and/or IV.

In another embodiment, the disclosure relates to the use of a compoundaccording to Formula I, II, IIIa, IIIb, and/or IV for altering theaesthetic appearance of skin associated with or affected by wrinklesand/or fine lines, wizened skin, a lack of elasticity and/or tonus ofthe skin, thinning of the dermis, degradation of collagen fibers,flaccid skin, thinned skin, and/or the internal degradation of the skinfollowing exposure to ultraviolet radiation.

In one embodiment, the present disclosure provides a cosmetic ordermopharmaceutical composition for altering the aesthetic appearance ofskin associated with or affected by, or for treating or preventing, askin condition/disorder accompanied by a loss of skin elasticity,wherein the composition comprises a compound according to Formula I, II,IIIa, IIIb, and/or IV.

In one embodiment, the present disclosure provides a cosmetic ordermopharmaceutical composition for altering the aesthetic appearance ofskin associated with or affected by, or for treating or preventing,acne, wherein the composition comprises a compound according to FormulaI, II, IIIa, IIIb, and/or IV.

In one embodiment, the present disclosure provides a cosmetic ordermopharmaceutical composition for treating or preventing deteriorationin skin viscoelasticity, wherein the composition comprises a compoundaccording to Formula I, II, IIIa, IIIb, and/or IV.

In one embodiment, the present disclosure provides a cosmetic ordermopharmaceutical composition for treating or preventing vitiligo(skin condition in which there is a loss of brown color (pigment) fromareas of skin), wherein the composition comprises a compound accordingto Formula I, II, IIIa, IIIb, and/or IV.

In one embodiment, the disclosure provides methods for increasing cellor tissue regeneration. Such methods include administering to avertebrate subject in need thereof a compound according to Formula I,II, IIIa, IIIb, and/or IV, or a dermatologically acceptable saltthereof.

In one embodiment, the present disclosure provides a cosmetic ordermopharmaceutical composition for activating or promotingproliferation and/or mobility of skin keratinocyte and/or dermisfibroblast, for example, to realize skin regeneration, wherein thecomposition comprises a compound according to Formula I, II, IIIa, IIIb,and/or IV.

In one embodiment, the present disclosure provides a cosmetic ordermopharmaceutical composition for increasing or improving epidermalcell repair activity, for example, in a human, wherein the compositioncomprises a compound according to Formula I, II, IIIa, IIIb, and/or IV.

In one embodiment, the present disclosure provides a cosmetic ordermopharmaceutical composition for increasing or improving the barrierfunction and/or viability of the skin, wherein the composition comprisesa compound according to Formula I, II, IIIa, IIIb, and/or IV.

In one embodiment, the present disclosure provides a cosmetic ordermopharmaceutical composition for increasing fibroblast proliferation,keratinocyte proliferation, and/or expression of collagen, or reducingcollagenase activity, wherein the composition comprises a compoundaccording to Formula I, II, IIIa, IIIb, and/or IV.

In another embodiment, the disclosure relates to the use of a compoundaccording to Formula I, II, IIIa, IIIb, and/or IV as a medicament fortreating or preventing a wound healing disorder in a mammal.

In another embodiment, the disclosure relates to the use of a compoundaccording to Formula I, II, IIIa, IIIb, and/or IV as a medicament fortreating or preventing a wound such as a bedsore in a mammal.

Some embodiments provided herein include cosmetic or dermopharmaceuticalcompositions comprising one or more of the compounds provided herein anda dermatologically acceptable carrier.

One embodiment provided herein includes compounds of Formula I:

or a dermatologically acceptable salt thereof.

In some embodiments of Formula I:

-   -   Ring A is a 7-12 membered heteroaryl, with the proviso that a        carbon atom on the ring is attached to the carbonyl carbon;    -   Ring B is selected from the group consisting of phenyl and a 5-6        membered heteroaryl, with the proviso that a carbon atom on the        ring is attached to the carbonyl carbon;    -   R¹ is a substituent attached to Ring A and is independently        selected at each occurrence from the group consisting of        unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR³, and        CN;    -   R² is a substituent attached to Ring B and is independently        selected at each occurrence from the group consisting of        unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃        haloalkyl, halide, —OR³, and CN;    -   each R³ is independently selected from the group consisting of        H, unsubstituted —C₁₋₆ alkyl, and —C₁₋₃ haloalkyl;    -   each R^(3b) is independently selected from the group consisting        of H and unsubstituted C₁₋₃ alkyl;    -   each n is 0 to 10; and    -   each m is 0 to 5.

Another embodiment provided herein includes compounds of Formula II:

or a dermatologically acceptable salt thereof.

In some embodiments of Formula II:

-   -   Ring C is a 5-6 membered heteroaryl, with the proviso that a        carbon atom on the ring is attached to the carbonyl carbon;    -   Ring D is selected from the group consisting of phenyl and a 5-6        membered heteroaryl, with the proviso that a carbon atom on the        ring is attached to the carbonyl carbon;    -   R⁴ is a substituent attached to Ring C and is independently        selected at each occurrence from the group consisting of        unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR⁶, and        CN;    -   R⁵ is a substituent attached to Ring D and is independently        selected at each occurrence from the group consisting of        unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃        haloalkyl, halide, —OR⁶, and CN;    -   each R⁶ is independently selected from the group consisting of        H, unsubstituted —C₁₋₆ alkyl, and —C₁₋₃ haloalkyl;    -   each R^(6b) is independently selected from the group consisting        of H and unsubstituted C₁₋₃ alkyl;    -   each q is 0 to 4; and    -   each p is 0 to 5.

Another embodiment provided herein includes compounds of Formula III:

or a dermatologically acceptable salt thereof.

In some embodiments of Formula III:

-   -   R⁷ is a substituent attached to the phenyl ring and is        independently selected at each occurrence from the group        consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(9a))₂,        —C₁₋₃ haloalkyl, halide, —OR⁹, and CN;    -   R⁸ is a substituent attached to the phenyl ring and is        independently selected at each occurrence from the group        consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(9a))₂,        —C₁₋₃ haloalkyl, halide, —OR⁹, and CN;    -   each R⁹ is independently selected from the group consisting of        H, unsubstituted —C₁₋₆ alkyl, and —C₁₋₃ haloalkyl;    -   each R^(9a) is independently selected from the group consisting        of H and unsubstituted C₁₋₃ alkyl; and    -   each q is 1 to 5; and    -   each p is 0 to 5.

Another embodiment provided herein includes compounds of Formula IIIa:

or a dermatologically acceptable salt thereof.

In some embodiments of Formula IIIa:

-   -   R¹⁰ is selected from the group consisting of H, unsubstituted        —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR¹³, and CN;    -   R¹¹ is selected from the group consisting of unsubstituted —C₁₋₆        alkyl, —CH₂OH, —CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl, halide, —OR¹³,        and CN;    -   R¹² is a substituent attached to the phenyl ring and is        independently selected at each occurrence from the group        consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,        —CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl, halide, —OR¹³, and CN;    -   each R¹³ is independently selected from the group consisting of        unsubstituted —C₁₋₆ alkyl, and —C₁₋₃ haloalkyl;    -   each R^(13b) is independently selected from the group consisting        of H and unsubstituted —C₁₋₃ alkyl; and    -   each q is 0 to 5.

Another embodiment provided herein includes compounds of Formula IIIb:

or a dermatologically acceptable salt thereof.

In some embodiments of Formula IIIb:

-   -   R¹⁴ is selected from the group consisting of unsubstituted —C₁₋₆        alkyl and —C₁₋₃ haloalkyl;    -   R¹⁵ is selected from the group consisting of unsubstituted —C₁₋₆        alkyl and —C₁₋₃ haloalkyl;    -   R¹⁶ is a substituent attached to the phenyl ring and is        independently selected at each occurrence from the group        consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,        —CH₂N(R^(17b))₂, —C₁₋₃ haloalkyl, halide, —OR′, and CN;    -   each R¹⁷ is independently selected from the group consisting of        unsubstituted —C₁₋₆ alkyl and —C₁₋₃ haloalkyl;    -   each R^(17b) is independently selected from the group consisting        of H and unsubstituted —C₁₋₃ alkyl; and    -   each q is 0 to 5.

Another embodiment provided herein includes compounds of Formula IV:

or a dermatologically acceptable salt thereof.

In some embodiments of Formula IV:

-   -   Ring F is

-   -   Ring G is selected from the group consisting of

and a 5-6 membered heteroaryl(R^(19d))_(z), with the proviso that acarbon atom on the heteroaryl ring is attached to the carbonyl carbon;

-   -   each R¹⁸ is a substituent attached to Ring F and is        independently selected at each occurrence from the group        consisting of —C₁₋₃ haloalkyl, halide, —OR²⁰, and CN;    -   R^(19a) is a substituent attached to the para position of phenyl        and is selected from the group consisting of H, unsubstituted        —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, F, Br, I,        —OR²⁰, and CN;    -   R^(19b) is a substituent attached to the meta or ortho position        of phenyl and is selected from the group consisting of H,        unsubstituted —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl,        halide, —OR²⁰, and CN;    -   R^(19c) is a substituent attached to the phenyl and is        independently selected at each occurrence from the group        consisting of —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, halide,        —OR²⁰, and CN;    -   R^(19d) is a substituent attached to the heteroaryl ring and is        independently selected at each occurrence from the group        consisting of —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, halide,        —OR²⁰, and CN;    -   each R²⁰ is independently selected from the group consisting of        H, unsubstituted —C₃₋₆ alkyl and —C₁₋₃ haloalkyl;    -   each R²¹ is independently selected from the group consisting of        H and unsubstituted —C₁₋₃ alkyl;    -   k is 0 to 5;    -   p is 0 to 13;    -   r is 1 to 5;    -   z is 0 to 4.

Some embodiments include stereoisomers of a compound of Formula I, II,IIIa, IIIb, and/or IV.

Some embodiments include prodrugs of a compound of Formula I, II, IIIa,IIIb, and/or IV. For example, prodrugs of a compound of Formula I, II,IIIa, IIIb, and/or IV can be prodrug polymer conjugates for delayedrelease or extended release.

Also provided herein are cosmetic or dermopharmaceutical compositionscomprising a compound of Formula I, II, IIIa, IIIb, and/or IV and adermatologically acceptable carrier, diluent, or excipient.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the disclosure, as claimed.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 is a line graph showing the average change in roughness frombaseline of test subjects skin after topical treatment of theperiorbital areas by compound #222 (0.05% in oil, 0.05% in PEG, 0.15% inoil, and 0.15% in PEG). Roughness was determined by Visioscan. Each datapoint is the average of 20 or 21 test subjects.

FIG. 2 is a line graph showing the average percent wrinkle reductionfrom baseline of test subjects skin after topical treatment of theperiorbital areas by compound #222 (0.05% in oil, 0.05% in PEG, 0.15% inoil, and 0.15% in PEG). Wrinkle reduction was determined by Visioscan.Each data point is the average of 20 or 21 test subjects.

DETAILED DESCRIPTION

Provided herein are γ-diketones useful for treating, protecting, andimproving the condition and/or aesthetic appearance of skin, forexample, treating, preventing, ameliorating, reducing and/oreliminating, and/or improving the appearance of fine lines and/orwrinkles of skin. The inventors have discovered that in someembodiments, application of the γ-diketones provided herein can increasecollagen replacement and retention, and can also, in some embodiments,increase cellular proliferation of the epidermis and dermis.

Cosmetic or dermopharmaceutical compositions comprising one or morecompounds according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii,II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/orIV, or a dermatologically acceptable salt thereof, and adermatologically acceptable carrier are also provided herein.

Compounds

Some embodiments of the present disclosure include compounds of Formula(I):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula I, Ring A is a 7-12 membered heteroaryl,wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula I, Ring A is a 7-12 membered heteroaryl,wherein a carbon atom on the benzene ring is attached to the carbonylcarbon.

In some embodiments of Formula I, Ring A is a 7-12 membered heteroaryl,wherein a carbon atom on the heteroaromatic ring is attached to thecarbonyl carbon.

In some embodiments of Formula I, Ring A is a 7-12 membered heteroaryl,wherein a carbon atom on the heterocyclic aliphatic ring is attached tothe carbonyl carbon.

In some embodiments of Formula I, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, with the provisothat a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula I, R¹ is a substituent attached to Ring Aand is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, and CN.

In some embodiments of Formula I, R¹ is a substituent attached to Ring Aand is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR³,and CN.

In some embodiments of Formula I, R² is a substituent attached to Ring Band is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula I, R² is a substituent attached to Ring Band is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula I, each R³ is independently selected fromthe group consisting of H, unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula I, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula I, n is 0 to 10. In some embodiments ofFormula I, n is 1 to 10.

In some embodiments of Formula I, m is 0 to 5.

In some embodiments of Formula I, m is 1 to 5.

In some embodiments of Formula I, Ring A is a 9-membered bicyclicheteroaryl ring containing 1-3 heteroatoms selected from the groupconsisting of N, O, and S.

In some embodiments of Formula I, Ring A is a 10-membered bicyclicheteroaryl ring containing 1-3 heteroatoms selected from the groupconsisting of N, O, and S.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of:

wherein, unless otherwise designated, the carbonyl carbon of Formula Ican form a bond with any unsubstituted carbon on Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of:

wherein the carbonyl carbon of Formula I can form a bond with anyunsubstituted carbon on Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of:

wherein the carbonyl carbon of Formula I can form a bond with anyunsubstituted carbon on the Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of:

wherein the carbonyl carbon of Formula I can form a bond with anyunsubstituted carbon on the Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of

wherein the carbonyl carbon of Formula I can form a bond with anyunsubstituted carbon on the Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of

wherein the carbonyl carbon of Formula I can form a bond with anyunsubstituted carbon on the Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of

wherein the carbonyl carbon of Formula I can form a bond with anyunsubstituted carbon on the Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of

In some embodiments, Ring A is selected from the group consisting of

Some embodiments of Formula I include compounds of Formula (Ia):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Ia, Ring A is

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, and CN.

In some embodiments of Formula Ia, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR³,and CN.

In some embodiments of Formula Ia, R^(2a) is a substituent attached tothe para position of phenyl and selected from the group consisting ofunsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, Cl,Br, I, —OR^(3a), and CN.

In some embodiments of Formula Ia, R^(2b) is one substituent attached tothe meta or ortho position of phenyl and selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃haloalkyl, halide, —OR′, and CN.

In some embodiments of Formula Ia, R^(2c) is a substituent attached tothe phenyl and are independently selected at each occurrence from thegroup consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, and CN; m is 2 to 5.

In some embodiments of Formula Ia, R^(2d) is a substituent attached tothe heteroaryl ring and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, and CN; s is 1 to 4.

In some embodiments of Formula Ia, R^(2e) is a substituent attached tothe heteroaryl ring and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, and CN; t is 1 to 4.

In some embodiments of Formula Ia, R^(2e) is a substituent attached tothe heteroaryl ring and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, and CN; t is 0 to 4.

In some embodiments of Formula Ia, R^(2f) is a substituent attached tothe heteroaryl ring and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, and CN; u is 1 to 3.

In some embodiments of Formula Ia, R^(2g) is a substituent attached tothe heteroaryl ring and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, and CN; v is 1 to 3.

In some embodiments of Formula Ia, R² is a substituent attached to theheteroaryl ring and are independently selected at each occurrence fromthe group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, and CN; v is 0 to 3.

In some embodiments of Formula Ia, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula Ia, each R^(3a) is independently selectedfrom the group consisting of unsubstituted —C₂₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula Ia, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ia, each W is independently N or C.

In some embodiments of Formula Ia, at least two W must be N.

In some embodiments of Formula Ia, each U is independently N or C.

In some embodiments of Formula Ia, at least one U must be N and at leastone U must be C.

In some embodiments of Formula Ia, G is NH or O.

In some embodiments of Formula Ia, each J is independently N or C.

In some embodiments of Formula Ia, at least one J must be C.

In some embodiments of Formula Ia, n is 0 to 7.

In some embodiments of Formula Ia, n is 1 to 7.

In some embodiments of Formula Ia, Ring A is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, t is 0.

In some embodiments of Formula Ia, at least one R^(2e) is a halide.

In some embodiments of Formula Ia, at least one R^(2e) is F.

In some embodiments of Formula Ia, at least one R^(2e) is Cl.

In some embodiments of Formula Ia, at least one R^(2e) is Me.

In some embodiments of Formula Ia, at least one R^(2e) is OH.

In some embodiments of Formula Ia, at least one R^(2e) is OMe.

In some embodiments of Formula Ia, at least one R^(2e) is CF₃.

In some embodiments of Formula Ia, at least one R^(2e) is CN.

In some embodiments of Formula Ia, t is 1 and R^(2e) is F.

In some embodiments of Formula Ia, t is 2 and both R^(2e) are F.

In some embodiments of Formula Ia, t is 1 and R^(2e) is Me.

In some embodiments of Formula Ia, t is 2 and both R^(2e) are Me.

In some embodiments of Formula Ia, t is 1 and R^(2e) is CF₃.

In some embodiments of Formula Ia, t is 2 and both R^(2e) are CF₃.

In some embodiments of Formula Ia, t is 1 and R^(2e) is OMe.

In some embodiments of Formula Ia, t is 2 and both R^(2e) are OMe.

In some embodiments of Formula Ia, t is 2 and one R^(2e) is F and theother R^(2e) is Me.

In some embodiments of Formula Ia, t is 2 and one R^(2e) is F and theother R^(2e) is CF₃.

In some embodiments of Formula Ia, t is 2 and one R^(2e) is F and theother R^(2e) is OMe.

In some embodiments of Formula Ia, t is 1 and R^(2e) is CN.

In some embodiments of Formula Ia, t is 2 and both R^(2e) are CN.

In some embodiments of Formula Ia, t is 2 and one R^(2e) is F and theother R^(2e) is CN.

In some embodiments of Formula Ia, at least one R^(2e) is —C₁₋₂ alkyl.

In some embodiments of Formula Ia, at least one R^(2e) is —C₁₋₃ alkyl.

In some embodiments of Formula Ia, at least one R^(2e) is —C₁₋₄ alkyl.

In some embodiments of Formula Ia, at least one R^(2e) is —C₁₋₅ alkyl.

In some embodiments of Formula Ia, at least one R^(2e) is —C₁₋₆ alkyl.

In some embodiments of Formula Ia, at least one R^(2e) is —C₂₋₆ alkyl.

In some embodiments of Formula Ia, at least one R^(2e) is —C₃₋₆ alkyl.

In some embodiments of Formula Ia, at least one R^(2e) is —C₄₋₆ alkyl.

In some embodiments of Formula Ia, at least one R^(2e) is —C₂₋₅ alkyl.

In some embodiments of Formula Ia, at least one R^(2e) is —C₃₋₄ alkyl.

In some embodiments of Formula Ia, at least one R^(2f) is halide.

In some embodiments of Formula Ia, at least one R^(2f) is F.

In some embodiments of Formula Ia, at least one R^(2f) is Cl.

In some embodiments of Formula Ia, at least one R^(2f) is Me.

In some embodiments of Formula Ia, at least one R^(2f) is OH.

In some embodiments of Formula Ia, at least one R^(2f) is OMe.

In some embodiments of Formula Ia, at least one R^(2f) is CF₃.

In some embodiments of Formula Ia, at least one R^(2f) is CN.

In some embodiments of Formula Ia, u is 1 and R^(2f) is F.

In some embodiments of Formula Ia, u is 2 and both R^(2f) are F.

In some embodiments of Formula Ia, u is 1 and R^(2f) is Me.

In some embodiments of Formula Ia, u is 2 and both R^(2f) are Me.

In some embodiments of Formula Ia, u is 1 and R^(2f) is CF₃.

In some embodiments of Formula Ia, u is 2 and both R^(2f) are CF₃.

In some embodiments of Formula Ia, u is 1 and R^(2f) is OMe.

In some embodiments of Formula Ia, u is 2 and both R^(2f) are OMe.

In some embodiments of Formula Ia, u is 2 and one R^(2f) is F and theother R^(2f) is Me.

In some embodiments of Formula Ia, u is 2 and one R^(2f) is F and theother R^(2f) is CF₃.

In some embodiments of Formula Ia, u is 2 and one R^(2f) is F and theother R^(2f) is OMe.

In some embodiments of Formula Ia, u is 1 and R^(2f) is CN.

In some embodiments of Formula Ia, u is 2 and both R^(2f) are CN.

In some embodiments of Formula Ia, u is 2 and one R^(2f) is F and theother R^(2f) is CN.

In some embodiments of Formula Ia, at least one R^(2f) is —C₁₋₂ alkyl.

In some embodiments of Formula Ia, at least one R^(2f) is —C₁₋₃ alkyl.

In some embodiments of Formula Ia, at least one R^(2f) is —C₁₋₄ alkyl.

In some embodiments of Formula Ia, at least one R^(2f) is —C₁₋₅ alkyl.

In some embodiments of Formula Ia, at least one R^(2f) is —C₁₋₆ alkyl.

In some embodiments of Formula Ia, at least one R^(2f) is —C₂₋₆ alkyl.

In some embodiments of Formula Ia, at least one R^(2f) is —C₃₋₆ alkyl.

In some embodiments of Formula Ia, at least one R^(2f) is —C₄₋₆ alkyl.

In some embodiments of Formula Ia, at least one R^(2f) is —C₂₋₅ alkyl.

In some embodiments of Formula Ia, at least one R^(2f) is —C₃₋₄ alkyl.

In some embodiments of Formula Ia, v is 0.

In some embodiments of Formula Ia, v is 1.

In some embodiments of Formula Ia, v is 2.

In some embodiments of Formula Ia, at least one R² is halide.

In some embodiments of Formula Ia, at least one R² is F.

In some embodiments of Formula Ia, at least one R² is Cl.

In some embodiments of Formula Ia, at least one R² is Me.

In some embodiments of Formula Ia, at least one R² is OH.

In some embodiments of Formula Ia, at least one R² is OMe.

In some embodiments of Formula Ia, at least one R² is CF₃.

In some embodiments of Formula Ia, at least one R² is CN.

In some embodiments of Formula Ia, v is 1 and R² is F.

In some embodiments of Formula Ia, v is 2 and both R^(2g) are F.

In some embodiments of Formula Ia, v is 1 and R^(2g) is Me.

In some embodiments of Formula Ia, v is 2 and both R^(2g) are Me.

In some embodiments of Formula Ia, v is 1 and R^(2g) is CF₃.

In some embodiments of Formula Ia, v is 2 and both R^(2g) are CF₃.

In some embodiments of Formula Ia, v is 1 and R^(2g) is OMe.

In some embodiments of Formula Ia, v is 2 and both R^(2g) are OMe.

In some embodiments of Formula Ia, v is 2 and one R² is F and the otherR² is Me.

In some embodiments of Formula Ia, v is 2 and one R² is F and the otherR^(2g) is CF₃.

In some embodiments of Formula Ia, v is 2 and one R² is F and the otherR² is OMe.

In some embodiments of Formula Ia, v is 1 and R^(2g) is CN.

In some embodiments of Formula Ia, v is 2 and both R^(2g) are CN.

In some embodiments of Formula Ia, v is 2 and one R^(2g) is F and theother R^(2g) is CN.

In some embodiments of Formula Ia, at least one R^(2g) is —C₁₋₂ alkyl.

In some embodiments of Formula Ia, at least one R^(2g) is —C₁₋₃ alkyl.

In some embodiments of Formula Ia, at least one R^(2g) is —C₁₋₄ alkyl.

In some embodiments of Formula Ia, at least one R^(2g) is —C₁₋₅ alkyl.

In some embodiments of Formula Ia, at least one R^(2g) is —C₁₋₆ alkyl.

In some embodiments of Formula Ia, at least one R^(2g) is —C₂₋₆ alkyl.

In some embodiments of Formula Ia, at least one R^(2g) is —C₃₋₆ alkyl.

In some embodiments of Formula Ia, at least one R^(2g) is —C₄₋₆ alkyl.

In some embodiments of Formula Ia, at least one R^(2g) is —C₂₋₅ alkyl.

In some embodiments of Formula Ia, at least one R^(2g) is —C₃₋₄ alkyl.

Some embodiments of Formula I include compounds of Formula (Ib):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Ib, Ring A is

In some embodiments of Formula Ib, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula Ib, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, and CN.

In some embodiments of Formula Ib, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR³,and CN.

In some embodiments of Formula Ib, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula Ib, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula Ib, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula Ib, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ib, each M is independently selected fromthe group consisting of N, C, S and O.

In some embodiments of Formula Ib, both M are not O.

In some embodiments of Formula Ib, both M are not C.

In some embodiments of Formula Ib, m is 0 to 5.

In some embodiments of Formula Ib, m is 1 to 5.

In some embodiments of Formula Ib, n is 0 to 10.

In some embodiments of Formula Ib, n is 1 to 10.

In some embodiments of Formula Ib, Ring A is selected from the groupconsisting of

Some embodiments of Formula I include compounds of Formula (Ic):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Ic, Ring A is

In some embodiments of Formula Ic, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula Ic, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, and CN.

In some embodiments of Formula Ic, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR³,and CN.

In some embodiments of Formula Ic, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula Ic, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula Ic, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula Ic, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ic, each M is independently selected fromthe group consisting of N, C, S and O.

In some embodiments of Formula Ic, if one M is C, the other M isselected from the group consisting of N, S, and O.

In some embodiments of Formula Ic, m is 0 to 5.

In some embodiments of Formula Ic, m is 1 to 5.

In some embodiments of Formula Ic, n is 0 to 10.

In some embodiments of Formula Ic, n is 1 to 10.

In some embodiments of Formula Ic, Ring A is selected from the groupconsisting of

Some embodiments of Formula I include compounds of Formula (Id):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Id, Ring A is

In some embodiments of Formula Id, Ring B is selected from the groupconsisting of

and a 5-6 membered heteroaryl(R^(2ee))_(y), wherein a carbon atom on thering is attached to the carbonyl carbon.

In some embodiments of Formula Id, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, and CN.

In some embodiments of Formula Id, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR³,and CN.

In some embodiments of Formula Id, R^(2a) is one substituent attached tothe para position of phenyl and is selected from the group consisting ofH, unsubstituted C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl,Cl, Br, I, —OR′, and CN.

In some embodiments of Formula Id, R^(2b) is one substituent attached tothe meta position of phenyl and is selected from the group consisting ofH, unsubstituted C₂₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, F,I, —OR³, and CN.

In some embodiments of Formula Id, R^(2c) is one substituent attached tothe ortho position of phenyl and is selected from the group consistingof unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl,F, Br, I, —OR³, and CN.

In some embodiments of Formula Id, R^(2dd) is a substituent attached tothe phenyl and is independently selected at each occurrence from thegroup consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, and CN; w is 1 to 5.

In some embodiments of Formula Id, R^(2ee) is a substituent attached tothe heteroaryl ring and is independently selected at each occurrencefrom the group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, and CN; y is 0 to 3.

In some embodiments of Formula Id, R^(2c) is a F.

In some embodiments of Formula Id, R^(2c) is a Me.

In some embodiments of Formula Id, R^(2c) is a OH.

In some embodiments of Formula Id, R^(2c) is a OMe.

In some embodiments of Formula Id, R^(2c) is a CF₃.

In some embodiments of Formula Id, R^(2c) is a CN.

In some embodiments of Formula Id, R^(2c) is a —C₁₋₂ alkyl.

In some embodiments of Formula Id, R^(2c) is a —C₁₋₃ alkyl.

In some embodiments of Formula Id, R^(2c) is a —C₁₋₄ alkyl.

In some embodiments of Formula Id, R^(2c) is a —C₁₋₅ alkyl.

In some embodiments of Formula Id, R^(2c) is a —C₁₋₆ alkyl.

In some embodiments of Formula Id, R^(2c) is a —C₂₋₆ alkyl.

In some embodiments of Formula Id, R^(2c) is a —C₃₋₆ alkyl.

In some embodiments of Formula Id, R^(2c) is a —C₄₋₆ alkyl.

In some embodiments of Formula Id, R^(2c) is a —C₂₋₅ alkyl.

In some embodiments of Formula Id, R^(2c) is a —C₃₋₄ alkyl.

In some embodiments of Formula Id, at least one R^(2dd) is F.

In some embodiments of Formula Id, at least one R^(2dd) is Cl.

In some embodiments of Formula Id, at least one R^(2dd) is Me.

In some embodiments of Formula Id, at least one R^(2dd) is OH.

In some embodiments of Formula Id, at least one R^(2dd) is OMe.

In some embodiments of Formula Id, at least one R^(2dd) is CF₃.

In some embodiments of Formula Id, at least one R^(2dd) is CN.

In some embodiments, of Formula Id, w is 2 to 5.

In some embodiments, of Formula Id, w is 1.

In some embodiments, of Formula Id, w is 2.

In some embodiments of Formula Id, w is 1 and R^(2dd) is F.

In some embodiments of Formula Id, w is 2 and both R^(2dd) are F.

In some embodiments of Formula Id, w is 1 and R^(2dd) is Me.

In some embodiments of Formula Id, w is 2 and both R^(2dd) are Me.

In some embodiments of Formula Id, w is 1 and R^(2dd) is CF₃.

In some embodiments of Formula Id, w is 2 and both R^(2dd) are CF₃.

In some embodiments of Formula Id, w is 1 and R^(2dd) is OMe.

In some embodiments of Formula Id, w is 2 and both R^(2dd) are OMe.

In some embodiments of Formula Id, w is 2 and one R^(2dd) is F and theother R^(2dd) is Me.

In some embodiments of Formula Id, w is 2 and one R^(2dd) is F and theother R^(2dd) is CF₃.

In some embodiments of Formula Id, w is 2 and one R^(2dd) is F and theother R^(2dd) is OMe.

In some embodiments of Formula Id, w is 1 and R^(2dd) is CN.

In some embodiments of Formula Id, w is 2 and both R^(2dd) are CN.

In some embodiments of Formula Id, w is 2 and one R^(2dd) is F and theother R^(2dd) is CN.

In some embodiments of Formula Id, at least one R^(2dd) is —C₁₋₂ alkyl.

In some embodiments of Formula Id, at least one R^(2dd) is —C₁₋₃ alkyl.

In some embodiments of Formula Id, at least one R^(2dd) is —C₁₋₄ alkyl.

In some embodiments of Formula Id, at least one R^(2dd) is —C₁₋₅ alkyl.

In some embodiments of Formula Id, at least one R^(2dd) is —C₁₋₆ alkyl.

In some embodiments of Formula Id, at least one R^(2dd) is —C₂₋₆ alkyl.

In some embodiments of Formula Id, at least one R^(2dd) is —C₃₋₆ alkyl.

In some embodiments of Formula Id, at least one R^(2dd) is —C₄₋₆ alkyl.

In some embodiments of Formula Id, at least one R^(2dd) is —C₂₋₅ alkyl.

In some embodiments of Formula Id, at least one R^(2dd) is —C₃₋₄ alkyl.

In some embodiments of Formula Id, y is 0.

In some embodiments of Formula Id, y is 1.

In some embodiments of Formula Id, y is 2.

In some embodiments of Formula Id, at least one R^(2ee) is halide.

In some embodiments of Formula Id, at least one R^(2ee) is F.

In some embodiments of Formula Id, at least one R^(2ee) is Cl.

In some embodiments of Formula Id, at least one R^(2ee) is Me.

In some embodiments of Formula Id, at least one R^(2ee) is OH.

In some embodiments of Formula Id, at least one R^(2ee) is OMe.

In some embodiments of Formula Id, at least one R^(2ee) is CF₃.

In some embodiments of Formula Id, at least one R^(2ee) is CN.

In some embodiments of Formula Id, y is 1 and R^(2ee) is F.

In some embodiments of Formula Id, y is 2 and both R^(2ee) are F.

In some embodiments of Formula Id, y is 1 and R^(2ee) is Me.

In some embodiments of Formula Id, y is 2 and both R^(2ee) are Me.

In some embodiments of Formula Id, y is 1 and R^(2ee) is CF₃.

In some embodiments of Formula Id, y is 2 and both R^(2ee) are CF₃.

In some embodiments of Formula Id, y is 1 and R^(2ee) is OMe.

In some embodiments of Formula Id, y is 2 and both R^(2ee) are OMe.

In some embodiments of Formula Id, y is 2 and one R^(2ee) is F and theother R^(2ee) is Me.

In some embodiments of Formula Id, y is 2 and one R^(2ee) is F and theother R^(2ee) is CF₃.

In some embodiments of Formula Id, y is 2 and one R^(2ee) is F and theother R^(2ee) is OMe.

In some embodiments of Formula Id, y is 1 and R^(2ee) is CN.

In some embodiments of Formula Id, y is 2 and both R^(2ee) are CN.

In some embodiments of Formula Id, y is 2 and one R^(2ee) is F and theother R^(2ee) is CN.

In some embodiments of Formula Id, at least one R^(2ee) is —C₁₋₂ alkyl.

In some embodiments of Formula Id, at least one R^(2ee) is —C₁₋₃ alkyl.

In some embodiments of Formula Id, at least one R^(2ee) is —C₁₋₄ alkyl.

In some embodiments of Formula Id, at least one R^(2ee) is —C₁₋₅ alkyl.

In some embodiments of Formula Id, at least one R^(2ee) is —C₁₋₆ alkyl.

In some embodiments of Formula Id, at least one R^(2ee) is —C₂₋₆ alkyl.

In some embodiments of Formula Id, at least one R^(2ee) is —C₃₋₆ alkyl.

In some embodiments of Formula Id, at least one R^(2ee) is —C₄₋₆ alkyl.

In some embodiments of Formula Id, at least one R^(2ee) is —C₂₋₅ alkyl.

In some embodiments of Formula Id, at least one R^(2ee) is —C₃₋₄ alkyl.

In some embodiments of Formula Id, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula Id, each R^(3a) is independently selectedfrom the group consisting of H, unsubstituted —C₂₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula Id, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Id, Q is S or NH.

In some embodiments of Formula Id, n is 0 to 5.

In some embodiments of Formula Id, n is 1 to 5.

In some embodiments of Formula Id, Ring A is selected from the groupconsisting of

In some embodiments of Formula Id, R^(2a) is H.

In some embodiments of Formula Id, R^(2b) is H.

In some embodiments of Formula Id, w is 0.

Some embodiments of Formula I include compounds of Formula (Ie):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Ie, Ring A is

In some embodiments of Formula Ie, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula Ie, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, and CN.

In some embodiments of Formula Ie, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR³,and CN.

In some embodiments of Formula Ie, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula Ie, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula Ie, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula Ie, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ie, each W is independently N or C.

In some embodiments of Formula Ie, at least one W must be N.

In some embodiments of Formula Ie, Q is S or NH.

In some embodiments of Formula Ie, m is 0 to 5.

In some embodiments of Formula Ie, m is 1 to 5.

In some embodiments of Formula Ie, n is 0 to 4.

In some embodiments of Formula Ie, n is 1 to 4.

In some embodiments of Formula Ie, Ring A is selected from the groupconsisting of

Some embodiments of Formula I include compounds of Formula (If):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula If, Ring A is

In some embodiments of Formula If, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula If, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR³,and CN.

In some embodiments of Formula If, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, and CN.

In some embodiments of Formula If, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula If, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula If, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula If, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula If, each W is independently N or C.

In some embodiments of Formula If, m is 0 to 5.

In some embodiments of Formula If, m is 1 to 5.

In some embodiments of Formula If, n is 0 to 5.

In some embodiments of Formula If, n is 1 to 5.

In some embodiments of Formula If, Ring A is selected from the groupconsisting of

Some embodiments of Formula I include compounds of Formula (Ig):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Ig, Ring A is

In some embodiments of Formula Ig, Ring B is selected from the groupconsisting of

and a 5-6 membered heteroaryl(R^(2d))_(s), wherein a carbon atom on thering is attached to the carbonyl carbon.

In some embodiments of Formula Ig, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, and CN.

In some embodiments of Formula Ig, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR³,and CN.

In some embodiments of Formula Ig, R^(2a) is one substituent attached tothe para position of phenyl and is selected from the group consisting ofunsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, F,I, —OR³, and CN.

In some embodiments of Formula Ig, R^(2b) is one substituent attached tothe meta or ortho position of phenyl and is selected from the groupconsisting of unsubstituted —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula Ig, R^(2c) is a substituent attached tothe phenyl and is independently selected at each occurrence from thegroup consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, and CN; m is 2-5.

In some embodiments of Formula Ig, R^(2d) is a substituent attached tothe heteroaryl ring and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, and CN; s is 1-3.

In some embodiments of Formula Ig, R^(2d) is a substituent attached tothe heteroaryl ring and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, and CN; s is 0-4.

In some embodiments of Formula Ig, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula Ig, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ig, Q is selected from the groupconsisting of O, S, and NH.

In some embodiments of Formula Ig, n is 0 to 5.

In some embodiments of Formula Ig, n is 1 to 5.

In some embodiments of Formula Ig, Ring A is selected from the groupconsisting of

In some embodiments of Formula Ig, R^(2a) is a F.

In some embodiments of Formula Ig, R^(2a) is a OH.

In some embodiments of Formula Ig, R^(2a) is a OMe.

In some embodiments of Formula Ig, at least one R^(2d) is —CH₂OH.

In some embodiments of Formula Ig, at least one R^(2d) is—CH₂N(R^(3b))₂.

In some embodiments of Formula Ig, at least one R^(2d) is —CH₂NH₂.

In some embodiments of Formula Ig, at least one R^(2d) is —CH₂NHMe.

In some embodiments of Formula Ig, at least one R^(2d) is —CH₂NMe₂.

In some embodiments of Formula Ig, at least one R^(2d) is —CH₂NHEt.

In some embodiments of Formula Ig, at least one R^(2d) is —CH₂N(Me)(Et).

In some embodiments of Formula Ig, at least one R^(2d) is —CH₂NEt₂.

Some embodiments of Formula I include compounds of Formula (Ih):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Ih, Ring A is

In some embodiments of Formula Ih, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula Ih, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, and CN.

In some embodiments of Formula Ih, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR³,and CN.

In some embodiments of Formula Ih, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula Ih, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula Ih, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula Ih, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ih, each W is independently N or C.

In some embodiments of Formula Ih, at least one W must be N.

In some embodiments of Formula Ih, Q is selected from the groupconsisting of O, S, and NH.

In some embodiments of Formula Ih, m is 0 to 5.

In some embodiments of Formula Ih, m is 1 to 5.

In some embodiments of Formula Ih, n is 0 to 4.

In some embodiments of Formula Ih, n is 1 to 4.

In some embodiments of Formula Ih, Ring A is selected from the groupconsisting of

Some embodiments of Formula I include compounds of Formula (Ii):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Ii, Ring A is

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula Ii, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula Ii, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, and CN.

In some embodiments of Formula Ii, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR³,and CN.

In some embodiments of Formula Ii, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula Ii, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃haloalkyl, halide, —OR³, and CN.

In some embodiments of Formula Ii, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula Ii, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ii, each W is independently N or C.

In some embodiments of Formula Ii, at least one W is C.

In some embodiments of Formula Ii, Q is selected from the groupconsisting of O, S, and N.

In some embodiments of Formula Ii, m is 0 to 5.

In some embodiments of Formula Ii, m is 1 to 5.

In some embodiments of Formula Ii, n is 0 to 7.

In some embodiments of Formula Ii, n is 1 to 7.

In some embodiments of Formula Ii, Ring A is selected from the groupconsisting of

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, —C₁₋₃ haloalkyl is CF₃.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R¹ is selected from the group consisting of F, Cl, Me, OMe, OH, CF₃,and CN.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, n is 0.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is a halide.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is F.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is Cl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is Me.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is OH.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is OMe.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is CF₃.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is CN.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, n is 0 to 8.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, n is 0 to 6.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, n is 0 to 4.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, n is 0 to 2.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R¹ is F; and n is 1.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R¹ is F; and n is 1 or 2.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R¹ is F; and n is 3 or 4.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R¹ is OH; and n is 1 or 2.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R¹ is OMe; and n is 1 or 2.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is —C₁₋₂ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is —C₁₋₃ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is —C₁₋₄ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is —C₁₋₅ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is —C₁₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is —C₂₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is —C₃₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, at least one R¹ is —C₄₋₆ alkyl.

In some embodiments, each R¹ is the same.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R¹ is independently selected at each occurrence from the groupconsisting of F, Cl, Me, OMe, OH, CF₃, and CN; and n is 1 or 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, Ring B isphenyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, Ring B isa 5-membered heteroaryl containing 1-3 heteroatoms selected from thegroup consisting of N, O, and S.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, Ring B isa 6-membered heteroaryl containing 1-2 nitrogen atoms.

In some embodiments of Formula Ia, at least one R^(2d), R^(2e), R^(2f)or R^(2g) is —CH₂OH.

In some embodiments of Formula Ia, Id, and Ig, at least one R^(2a),R^(2b), or R^(2c) is —CH₂OH.

In some embodiments of Formula Id, at least one R^(2dd) or R^(2ee) is—CH₂OH.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ig, Ih, and Ii, atleast one R² is —CH₂OH.

In some embodiments of Formula Ia, at least one R^(2d), R^(2e), R^(2f),or R^(2g) is —CH₂N(R^(3b))₂.

In some embodiments of Formula Ia, Id, and Ig, at least one R^(2a),R^(2b), or R^(2c) is —CH₂N(R^(3b))₂.

In some embodiments of Formula Id, at least one R^(2dd) or R^(2ee) is—CH₂N(R^(3b))₂.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ig, Ih, and Ii, atleast one R² is —CH₂N(R^(3b))₂.

In some embodiments of Formula Ia, at least one R^(2d), R^(2e), R^(2f),or R^(2g) is —CH₂NH₂.

In some embodiments of Formula Ia, Id, and Ig, at least one R^(2a),R^(2b), or R^(2c) is —CH₂NH₂.

In some embodiments of Formula Id, at least one R^(2dd) or R^(2ee) is—CH₂NH₂.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ig, Ih, and Ii, atleast one R² is —CH₂NH₂.

In some embodiments of Formula Ia, at least one R^(2d), R^(2e), R^(2f),or R^(2g) is —CH₂NHMe.

In some embodiments of Formula Ia, Id, and Ig, at least one R^(2a),R^(2b), or R^(2c) is —CH₂NHMe.

In some embodiments of Formula Id, at least one R^(2dd) or R^(2ee) is—CH₂NHMe.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ig, Ih, and Ii, atleast one R² is —CH₂NHMe.

In some embodiments of Formula Ia, at least one R^(2d), R^(2e), R^(2f),or R^(2g) is —CH₂NMe₂.

In some embodiments of Formula Ia, Id, and Ig, at least one R^(2a),R^(2b), or R^(2c) is —CH₂NMe₂.

In some embodiments of Formula Id, at least one R^(2dd) or R^(2ee) is—CH₂NMe₂.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ig, Ih, and Ii, atleast one R² is —CH₂NMe₂.

In some embodiments of Formula Ia, at least one R^(2d), R^(2e), R^(2f),or R^(2g) is —CH₂NHEt.

In some embodiments of Formula Ia, Id, and Ig, at least one R^(2a),R^(2b), or R^(2c) is —CH₂NHEt.

In some embodiments of Formula Id, at least one R^(2dd) or R^(2ee) is—CH₂NHEt.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ig, Ih, and Ii, atleast one R² is —CH₂NHEt.

In some embodiments of Formula Ia, at least one R^(2d), R^(2e), R^(2f),or R^(2g) is —CH₂N(Me)(Et).

In some embodiments of Formula Ia, Id, and Ig, at least one R^(2a),R^(2b), or R^(2c) is —CH₂N(Me)(Et).

In some embodiments of Formula Id, at least one R^(2dd) or R^(2ee) is—CH₂N(Me)(Et).

In some embodiments of Formula I, Ib, Ic, Ie, If, Ig, Ih, and Ii, atleast one R² is —CH₂N(Me)(Et).

In some embodiments of Formula Ia, at least one R^(2d), R^(2e), R^(2f),or R^(2g) is —CH₂NEt₂.

In some embodiments of Formula Ia, Id, and Ig, at least one R^(2a),R^(2b), or R^(2c) is —CH₂NEt₂.

In some embodiments of Formula Id, at least one R^(2dd) or R^(2ee) is—CH₂NEt₂.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ig, Ih, and Ii, atleast one R² is —CH₂NEt₂.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is independently selected at each occurrence from the groupconsisting of F, Cl, Me, OMe, OH, CF₃, and CN.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, m is 0.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is halide.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is F.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is Cl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is Me.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is OH.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is OMe.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is CF₃.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is CN.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, m is 0 to4.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, m is 0 to2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, m is 1.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is F;and m is 1.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is F;and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is Me;and m is 1.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is Me;and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is CF₃;and m is 1.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is CF₃;and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is OMe;and m is 1.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is OMe;and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is Fand Me; and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is Fand CF₃; and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is Fand OMe; and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is CN;and m is 1.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is CN;and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, R² is Fand CN; and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is —C₁₋₂ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is —C₁₋₃ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is —C₁₋₄ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is —C₁₋₅ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is —C₁₋₆ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is —C₂₋₆ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is —C₃₋₆ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, at leastone R² is —C₄₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R³ is —C₁₋₂ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R³ is —C₁₋₃ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R³ is —C₁₋₄ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R³ is —C₁₋₅ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R³ is —C₁₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R³ and/or R^(3a) is —C₂₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R³ and/or R^(3a) is —C₃₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R³ and/or R^(3a) is —C₄₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R³ and/or R^(3a) is —C₂₋₅ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, andIi, R³ and/or R^(3a) is —C₃₋₄ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, Ring B isa phenyl or 6-membered heteroaryl; R² is selected from the groupconsisting of F, Cl, Me, OMe, OH, CF₃, and CN; m is 1; and R² isattached to an ortho carbon of the 6-membered ring.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, Ring B isa phenyl; R² is selected from the group consisting of F, Cl, Me, OMe,OH, CF₃; and CN; m is 1; and R² is attached to an ortho position of thephenyl ring.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii, Ring B isa pyridine; R² is selected from the group consisting of F, Cl, Me, OMe,OH, CF₃, and CN; m is 1; and R² is attached to an ortho carbon of thepyridine ring.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula I, Ib, Ic, Ie, If, Ih, and Ii,can form a bond with any unsubstituted carbon on the Ring B.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula I, Ib, Ic, Ie, If, Ih, and Ii,can form a bond with any unsubstituted carbon on the Ring B.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula I, Ib, Ic, Ie, If, Ih, and Ii,can form a bond with any unsubstituted carbon on the Ring B.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii,

is selected from the group consisting of

and m is 1 or 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii,

is selected from the group consisting of

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii,

is selected from the group consisting of

and m is 0 to 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii,

is selected from the group consisting of

and m is 0.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii,

is selected from the group consisting of

and m is 0 to 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and Ii,

is selected from the group consisting of

and m is 0.

In some embodiments of Formula Ia and Id, R^(2a) is a Cl.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a Me.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a CF₃.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a CN.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a Me.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a CF₃.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a CN.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a —C₁₋₂ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a —C₁₋₃ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a —C₁₋₄ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a —C₁₋₅ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a —C₁₋₆ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a —C₂₋₆ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a —C₃₋₆ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a —C₄₋₆ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a —C₂₋₅ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2a) is a —C₃₋₄ alkyl.

In some embodiments of Formula Ia and Ig, R^(2b) is a halide.

In some embodiments of Formula Ia, Id, and Ig, R^(2b) is a F.

In some embodiments of Formula Ia and Ig, R^(2b) is a Cl.

In some embodiments of Formula Ia, R^(2b) is a Me.

In some embodiments of Formula Id and Ig, R^(2b) is a OH.

In some embodiments of Formula Id and Ig, R^(2b) is a OMe.

In some embodiments of Formula Ia, Id, and Ig, R^(2b) is a CF₃.

In some embodiments of Formula Ia, Id, and Ig, R^(2b) is a CN.

In some embodiments of Formula Ia, R^(2b) is a —C₁₋₂ alkyl.

In some embodiments of Formula Ia, R^(2b) is a —C₁₋₃ alkyl.

In some embodiments of Formula Ia, R^(2b) is a —C₁₋₄ alkyl.

In some embodiments of Formula Ia, R^(2b) is a —C₁₋₅ alkyl.

In some embodiments of Formula Ia, R^(2b) is a —C₁₋₆ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2b) is a —C₂₋₆ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2b) is a —C₃₋₆ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2b) is a —C₄₋₆ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2b) is a —C₂₋₅ alkyl.

In some embodiments of Formula Ia, Id, and Ig, R^(2b) is a —C₃₋₄ alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is halide.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is F.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is Cl.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is Me.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is OH.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is OMe.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is CF₃.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is CN.

In some embodiments of Formula Ia and Ig, R^(2c) is a F.

In some embodiments of Formula Ia and Ig, R^(2c) is F and m is 1.

In some embodiments of Formula Ia and Ig, R^(2c) is Me and m is 1.

In some embodiments of Formula Ia and Ig, R^(2c) is Me and m is 2.

In some embodiments of Formula Ia and Ig, R^(2c) is CF₃ and m is 1.

In some embodiments of Formula Ia and Ig, R^(2c) is CF₃ and m is 2.

In some embodiments of Formula Ia and Ig, R^(2c) is OMe and m is 1.

In some embodiments of Formula Ia and Ig, R^(2c) is OMe and m is 2.

In some embodiments of Formula Ia and Ig, m is 2 and one R^(2c) is F andthe other R^(2c) is Me.

In some embodiments of Formula Ia and Ig, m is 2 and one R^(2c) is F andthe other R^(2c) is CF₃.

In some embodiments of Formula Ia and Ig, m is 2 and one R^(2c) is F andthe other R^(2c) is OMe.

In some embodiments of Formula Ia and Ig, R^(2c) is CN and m is 1.

In some embodiments of Formula Ia and Ig, R^(2c) is CN and m is 2.

In some embodiments of Formula Ia and Ig, m is 2 and one R^(2c) is F andthe other R^(2c) is CN.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is —C₁₋₂alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is —C₁₋₃alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is —C₁₋₄alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is —C₁₋₅alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is —C₁₋₆alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is —C₂₋₆alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is —C₃₋₆alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is —C₄₋₆alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is —C₂₋₅alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2c) is —C₃₋₄alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is halide.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is F.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is Cl.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is Me.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is OH.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is OMe.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is CF₃.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is CN.

In some embodiments of Formula Ia and Ig, s is 1 and R^(2d) is F.

In some embodiments of Formula Ia and Ig, s is 2 and both R^(2d) are F.

In some embodiments of Formula Ia and Ig, s is 1 and R^(2d) is Me.

In some embodiments of Formula Ia and Ig, s is 2 and both R^(2d) are Me.

In some embodiments of Formula Ia and Ig, s is 1 and R^(2d) is CF₃.

In some embodiments of Formula Ia and Ig, s is 2 and both R^(2d) areCF₃.

In some embodiments of Formula Ia and Ig, s is 1 and R^(2d) is OMe.

In some embodiments of Formula Ia and Ig, s is 2 and both R^(2d) areOMe.

In some embodiments of Formula Ia and Ig, s is 2 and one R^(2d) is F andthe other R^(2d) is Me.

In some embodiments of Formula Ia and Ig, s is 2 and one R^(2d) is F andthe other R^(2d) is CF₃.

In some embodiments of Formula Ia and Ig, s is 2 and one R^(2d) is F andthe other R^(2d) is OMe.

In some embodiments of Formula Ia and Ig, s is 1 and R^(2d) is CN.

In some embodiments of Formula Ia and Ig, s is 2 and both R^(2d) are CN.

In some embodiments of Formula Ia and Ig, s is 2 and one R^(2d) is F andthe other R^(2d) is CN.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is —C₁₋₂alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is —C₁₋₃alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is —C₁₋₄alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is —C₁₋₅alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is —C₁₋₆alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is —C₂₋₆alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is —C₃₋₆alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is —C₄₋₆alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is —C₂₋₅alkyl.

In some embodiments of Formula Ia and Ig, at least one R^(2d) is —C₃₋₄alkyl.

Some embodiments of the present disclosure include compounds of Formula(II):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula II, Ring C is a 5-6 membered heteroaryl,wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula II, Ring D is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula II, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR⁶, and CN.

In some embodiments of Formula II, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR⁶,and CN.

In some embodiments of Formula II, each R⁵ is a substituent attached toRing D and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, and CN.

In some embodiments of Formula II, each R⁵ is a substituent attached toRing D and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, halide, —OR⁶, and CN.

In some embodiments of Formula II, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula II, each R^(6b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula II, each q is 0 to 4.

In some embodiments of Formula II, each q is 1 to 4.

In some embodiments of Formula II, each p is 0 to 5.

In some embodiments of Formula II, each p is 1 to 5.

In some embodiments of Formula II, Ring C is a 5-membered heteroarylring containing 1-3 heteroatoms selected from the group consisting of N,O, and S.

In some embodiments of Formula II,

is selected from the group consisting of

and p is 0 to 2.

In some embodiments of Formula II, p is 0.

In some embodiments of Formula II,

is

In some embodiments of Formula II, Ring C is a 6-membered heteroarylring containing 1-2 nitrogens.

In some embodiments of Formula II,

is selected from the group consisting of

and p is 0 to 2.

In some embodiments of Formula II,

is

In some embodiments of Formula II, each R⁴ is independently selectedfrom the group consisting of F, Cl, Me, OMe, OH, CF₃, and CN.

In some embodiments of Formula II, Ring C is selected from the groupconsisting of:

In some embodiments of Formula II, Ring D is a phenyl or 6-memberedheteroaryl; R⁵ is selected from the group consisting of F, Cl, Me, OMe,OH, CF₃ and CN; q is 1; and R⁵ is attached to an ortho carbon of the6-membered ring.

In some embodiments of Formula II, Ring D is a phenyl, R⁵ is selectedfrom the group consisting of F, Cl, Me, OMe, OH, CF₃ and CN; q is 1; andR⁵ is attached to an ortho position of the phenyl ring.

In some embodiments of Formula II, Ring D is a pyridine, R⁵ is selectedfrom the group consisting of F, Cl, Me, OMe, OH, CF₃ and CN; q is 1; andR⁵ is attached to an ortho carbon of the pyridine ring.

In some embodiments of Formula II,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula II can form a bond with anyunsubstituted carbon on the Ring D; and q is 1 or 2.

In some embodiments of Formula II, q is 0.

In some embodiments of Formula II,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula II can form a bond with anyunsubstituted carbon on the Ring D.

In some embodiments of Formula II,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula II can form a bond with anyunsubstituted carbon on the Ring D.

Some embodiments of Formula II include compounds of Formula (Ha):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIa, Ring C is

In some embodiments of Formula IIa, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIa, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR⁶, and CN.

In some embodiments of Formula IIa, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR⁶,and CN.

In some embodiments of Formula IIa, R^(5a) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, halide, —OR^(6a), and CN; j is 1 to 5.

In some embodiments of Formula IIa, R^(5b) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, F, I, —OR′, and CN; k is 1 to 4.

In some embodiments of Formula IIa, R^(5c) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, and CN; x is 1 to 3.

In some embodiments of Formula IIa, R^(5c) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, halide, —OR⁶, and CN; x is 0 to 3.

In some embodiments of Formula IIa, x is 0.

In some embodiments of Formula IIa, R^(5d) is a substituent attached tothe ring and are independently selected at each occurrence from thegroup consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, and CN; z is 1 or 2.

In some embodiments of Formula IIa, R^(5c) is a substituent attached tothe ring and are independently selected at each occurrence from thegroup consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR⁶, and CN; s is 1 to 3.

In some embodiments of Formula IIa, R^(5e) is a substituent attached tothe ring and are independently selected at each occurrence from thegroup consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, and CN; s is 0 to 3.

In some embodiments of Formula IIa, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula IIa, each R^(6a) is independentlyselected from the group consisting of H, unsubstituted —C₂₋₆ alkyl and—C₁₋₃ haloalkyl.

In some embodiments of Formula IIa, each R^(6b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIa, each A is independently N or C.

In some embodiments of Formula IIa, at least two A must be N.

In some embodiments of Formula IIa, each J is independently N or C.

In some embodiments of Formula IIa, at least one J must be N and atleast one J must be C.

In some embodiments of Formula IIa, each U is independently N or C.

In some embodiments of Formula IIa, at least one U must be C.

In some embodiments of Formula IIa, Q is O or N.

In some embodiments of Formula IIa, p is 0 to 4.

In some embodiments of Formula IIa, p is 1 to 4.

In some embodiments of Formula IIa, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIa, Ring D is selected from the groupconsisting of:

Some embodiments of Formula II include compounds of Formula (In):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIb, Ring C is

In some embodiments of Formula IIb, Ring D is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIb, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR′, and CN.

In some embodiments of Formula IIb, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR^(6a), and CN.

In some embodiments of Formula IIb, each R⁵ is a substituent attached toRing D and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, and CN.

In some embodiments of Formula IIb, each R⁵ is a substituent attached toRing D and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, halide, —OR⁶, and CN.

In some embodiments of Formula IIb, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, and —C₁₋₃haloalkyl.

In some embodiments of Formula IIb, each R^(6a) is independentlyselected from the group consisting of unsubstituted —C₁₋₆ alkyl and—C₁₋₃ haloalkyl.

In some embodiments of Formula IIb, each R^(6b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIb, each A is independently N or C.

In some embodiments of Formula IIb, at least two A must be N.

In some embodiments of Formula IIb, p is 0 to 3.

In some embodiments of Formula IIb, p is 1 to 3.

In some embodiments of Formula IIb, q is 1 to 5.

In some embodiments of Formula IIb, q is 0 to 5.

In some embodiments of Formula IIb, Ring C is selected from the groupconsisting of

In some embodiments of Formula II and IIb, Ring D is phenyl.

In some embodiments of Formula II and IIb,

is selected from the group consisting of

and q is 1 or 2.

In some embodiments of Formula II and IIb,

is selected from the group consisting of

In some embodiments of Formula II and IIb, Ring D is a 5-memberedheteroaryl containing 1-3 heteroatoms selected from the group consistingof N, O, and S.

In some embodiments of Formula II and IIb,

is selected

from the group consisting of and q is 0 to 2.

In some embodiments of Formula II and IIb,

is selected from the group consisting of

In some embodiments of Formula II and IIb, Ring D is a 6-memberedheteroaryl containing 1-2 nitrogen atoms.

In some embodiments of Formula II and IIb,

is selected from the group consisting of

and q is 0 to 2.

In some embodiments of Formula II and IIb,

is selected from the group consisting of

In some embodiments of Formula II and IIb, at least one R⁵ is —CH₂OH.

In some embodiments of Formula II and IIb, at least one R⁵ is—CH₂N(R^(3b))₂.

In some embodiments of Formula II and IIb, at least one R⁵ is —CH₂NH₂.

In some embodiments of Formula II and IIb, at least one R⁵ is —CH₂NHMe.

In some embodiments of Formula II and IIb, at least one R⁵ is —CH₂NMe₂.

In some embodiments of Formula II and IIb, at least one R⁵ is —CH₂NHEt.

In some embodiments of Formula II and IIb, at least one R⁵ is—CH₂N(Me)(Et).

In some embodiments of Formula II and IIb, at least one R⁵ is —CH₂NEt₂.

In some embodiments of Formula II and IIb, each R⁵ is independentlyselected from the group consisting of F, Cl, Me, OMe, OH, CF₃, and CN.

In some embodiments of Formula II and IIb, R⁵ is a halide.

In some embodiments of Formula II and IIb, R⁵ is F.

In some embodiments of Formula II and IIb, R⁵ is Cl.

In some embodiments of Formula II and IIb, R⁵ is Me.

In some embodiments of Formula II and IIb, R⁵ is OH.

In some embodiments of Formula II and IIb, R⁵ is OMe.

In some embodiments of Formula II and IIb, R⁵ is CF₃.

In some embodiments of Formula II and IIb, R⁵ is CN.

In some embodiments of Formula II and IIb, q is 1-4.

In some embodiments of Formula II and IIb, q is 1-2.

In some embodiments of Formula II and IIb, q is 0.

In some embodiments of Formula II and IIb, q is 1.

In some embodiments of Formula II and IIb, q is 2.

In some embodiments of Formula II and IIb, R⁵ is F; and q is 1.

In some embodiments of Formula II and IIb, R⁵ is F; and q is 2.

In some embodiments of Formula II and IIb, R⁵ is Me; and q is 1.

In some embodiments of Formula II and IIb, R⁵ is Me; and q is 2.

In some embodiments of Formula II and IIb, R⁵ is CF₃; and q is 1.

In some embodiments of Formula II and IIb, R⁵ is CF₃; and q is 2.

In some embodiments of Formula II and IIb, R⁵ is OMe; and q is 1.

In some embodiments of Formula II and IIb, R⁵ is OMe; and q is 2.

In some embodiments of Formula II and IIb, R⁵ is F and Me; and q is 2.

In some embodiments of Formula II and IIb, R⁵ is F and CF₃; and q is 2.

In some embodiments of Formula II and IIb, R⁵ is F and OMe; and q is 2.

In some embodiments of Formula II and IIb, R⁵ is CN; and q is 1.

In some embodiments of Formula II and IIb, R⁵ is CN; and q is 2.

In some embodiments of Formula II and IIb, R⁵ is F and CN; and q is 2.

In some embodiments of Formula II and IIb, at least one R⁵ is —C₁₋₂alkyl.

In some embodiments of Formula II and IIb, at least one R⁵ is —C₁₋₃alkyl.

In some embodiments of Formula II and IIb, at least one R⁵ is —C₁₋₄alkyl.

In some embodiments of Formula II and IIb, at least one R⁵ is —C₁₋₅alkyl.

In some embodiments of Formula II and IIb, at least one R⁵ is —C₁₋₆alkyl.

In some embodiments of Formula II and IIb, at least one R⁵ is —C₂₋₆alkyl.

In some embodiments of Formula II and IIb, at least one R⁵ is —C₃₋₆alkyl.

In some embodiments of Formula II and IIb, at least one R⁵ is —C₄₋₆alkyl.

In some embodiments of Formula II and IIb, at least one R⁵ is —C₂₋₅alkyl.

In some embodiments of Formula II and IIb, at least one R⁵ is —C₃₋₅alkyl.

Some embodiments of Formula II include compounds of Formula (IIc):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIc, Ring C is

In some embodiments of Formula IIc, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIc, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR⁶, and CN.

In some embodiments of Formula IIc, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR⁶,and CN.

In some embodiments of Formula IIc, R^(5a) is one substituent attachedto the para position of phenyl and is selected from the group consistingof unsubstituted —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₂₋₃ haloalkyl,iodide, —OR′, and CN.

In some embodiments of Formula IIc, R^(5b) is one substituent attachedto the meta position of phenyl and is selected from the group consistingof unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₂₋₃ haloalkyl,halide, —OR′, and CN.

In some embodiments of Formula IIc, R^(5c) is one substituent attachedto the ortho position of phenyl and is selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, F, Br, I, —OR^(6a), and CN.

In some embodiments of Formula IIc, R^(5d) is a substituent attached tothe phenyl and is independently selected at each occurrence from thegroup consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR^(6a), and CN; z is 2 to 5.

In some embodiments of Formula IIc, R^(5e) is a substituent attached tothe ring and is selected from the group consisting of unsubstituted—C₂₋₅ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, F, I, —OR⁶, andCN; s is 1.

In some embodiments of Formula IIc, R^(5f) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, F, Br, I, —OR⁶, and CN; t is 1 or 2.

In some embodiments of Formula IIc, R^(5f) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, F, Br, I, —OR⁶, and CN; t is 0 to 2.

In some embodiments of Formula IIc, R^(5g) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, halide, —OR⁶, and CN; u is 1 to 3.

In some embodiments of Formula IIc, R^(5h) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, and CN; v is 1 or 2.

In some embodiments of Formula IIc, R^(5h) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, halide, —OR⁶, and CN; v is 0 to 2.

In some embodiments of Formula IIc, R^(5i) is substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of H, H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, and CN; w is 1 to 4.

In some embodiments of Formula IIc, R^(5i) is substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, and CN; w is 0 to 4.

In some embodiments of Formula IIc, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, and —C₁₋₃haloalkyl.

In some embodiments of Formula IIc, each R^(6a) is independentlyselected from the group consisting of unsubstituted —C₂₋₆ alkyl and—C₁₋₃ haloalkyl.

In some embodiments of Formula IIc, each R^(6b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIc, each U is independently N or C.

In some embodiments of Formula IIc, at least one U must be C.

In some embodiments of Formula IIc, Q is S or 0.

In some embodiments of Formula IIc, at least one U must be N and atleast one U must be C.

In some embodiments of Formula IIc, p is 0 to 3.

In some embodiments of Formula IIc, p is 1 to 3.

In some embodiments of Formula IIc, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIc, t is 0.

In some embodiments of Formula IIc, v is 0.

In some embodiments of Formula IIc, w is 0.

In some embodiments of Formula IIc, R^(5a), R^(5b), or R^(5c) is a CN.

In some embodiments of Formula IIc, R^(5b) or R^(5c) is a halide.

In some embodiments of Formula IIc, R^(5b) or R^(5c) is a F.

In some embodiments of Formula IIc, R^(5b) is a Cl.

In some embodiments of Formula IIc, R^(5b) or R^(5c) is a Me.

In some embodiments of Formula IIc, R^(5c) is a CF₃.

In some embodiments of Formula IIc, R^(5b) or R^(5c) is a —C₁₋₂ alkyl.

In some embodiments of Formula IIc, R^(5b) or R^(5c) is a —C₁₋₃ alkyl.

In some embodiments of Formula IIc, R^(5b) or R^(5c) is a —C₁₋₄ alkyl.

In some embodiments of Formula IIc, R^(5b) or R^(5c) is a —C₁₋₅ alkyl.

In some embodiments of Formula IIc, R^(5b) or R^(5c) is a —C₁₋₆ alkyl.

In some embodiments of Formula IIc, R^(5a), R^(5b), or R^(5c) is a —C₂₋₆alkyl.

In some embodiments of Formula IIc, R^(5a), R^(5b), or R^(5c) is a —C₃₋₆alkyl.

In some embodiments of Formula IIc, R^(5a), R^(5b), or R^(5c) is a —C₄₋₆alkyl.

In some embodiments of Formula IIc, R^(5a), R^(5b), or R^(5c) is a —C₂₋₅alkyl.

In some embodiments of Formula IIc, R^(5a), R^(5b), or R^(5c) is a —C₃₋₅alkyl.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is halide.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is F.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is Cl.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is Me.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is OH.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is OMe.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is CF 3.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is CN.

In some embodiments of Formula IIc, t is 1.

In some embodiments of Formula IIc, t is 2.

In some embodiments of Formula IIc, t is 1 and R^(5f) is F.

In some embodiments of Formula IIc, t is 2 and both R^(5f) are F.

In some embodiments of Formula IIc, t is 1 and R^(5f) is Me.

In some embodiments of Formula IIc, t is 2 and both R^(5f) are Me.

In some embodiments of Formula IIc, t is 1 and R^(5f) is CF₃.

In some embodiments of Formula IIc, t is 2 and both R^(5f) are CF₃.

In some embodiments of Formula IIc, t is 1 and R^(5f) is OMe.

In some embodiments of Formula IIc, t is 2 and both R^(5f) are OMe.

In some embodiments of Formula IIc, t is 2 and one R^(5f) is F and theother R^(5f) is OMe.

In some embodiments of Formula IIc, t is 2 and one R^(5f) is F and theother R^(5f) is CF₃.

In some embodiments of Formula IIc, t is 2 and one R^(5f) is F and theother R^(5f) is OMe.

In some embodiments of Formula IIc, t is 1 and R^(5f) is CN.

In some embodiments of Formula IIc, t is 2 and both R^(5f) are CN.

In some embodiments of Formula IIc, t is 2 and one R^(5f) is F and theother R^(5f) is CN.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is —C₁₋₂ alkyl.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is —C₁₋₃ alkyl.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is —C₁₋₄ alkyl.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is —C₁₋₅ alkyl.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h)or R^(5i) is —C₁₋₆ alkyl.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h)or R^(5i) is C₂₋₆ alkyl.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h)or R^(5i) is C₃₋₆ alkyl.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h)or R^(5i) is C₄₋₆ alkyl.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h)or R^(5i) is C₂₋₅ alkyl.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h)or R^(5i) is C₃₋₅ alkyl.

In some embodiments of Formula IIc, u is 1.

In some embodiments of Formula IIc, u is 2.

In some embodiments of Formula IIc, u is 1 and R^(5g) is F.

In some embodiments of Formula IIc, u is 2 and both R^(5g) are F.

In some embodiments of Formula IIc, u is 1 and R^(5g) is Me.

In some embodiments of Formula IIc, u is 2 and both R^(5g) are Me.

In some embodiments of Formula IIc, u is 1 and R^(5g) is CF₃.

In some embodiments of Formula IIc, u is 2 and both R^(5g) are CF₃.

In some embodiments of Formula IIc, u is 1 and R^(5g) is OMe.

In some embodiments of Formula IIc, u is 2 and both R^(5g) are OMe.

In some embodiments of Formula IIc, u is 2 and one R^(5g) is F and theother R^(5g) is OMe.

In some embodiments of Formula IIc, u is 2 and one R^(5g) is F and theother R^(5g) is CF₃.

In some embodiments of Formula IIc, u is 2 and one R^(5g) is F and theother R^(5g) is OMe.

In some embodiments of Formula IIc, u is 1 and R^(5g) is CN.

In some embodiments of Formula IIc, u is 2 and both R^(5g) are CN.

In some embodiments of Formula IIc, u is 2 and one R^(5g) is F and theother R^(5g) is CN.

In some embodiments of Formula IIc, v is 1.

In some embodiments of Formula IIc, v is 2.

In some embodiments of Formula IIc, v is 1 and R^(5h) is F.

In some embodiments of Formula IIc, v is 2 and both R^(5h) are F.

In some embodiments of Formula IIc, v is 1 and R^(5h) is Me.

In some embodiments of Formula IIc, v is 2 and both R^(5h) are Me.

In some embodiments of Formula IIc, v is 1 and R^(5h) is CF₃.

In some embodiments of Formula IIc, v is 2 and both R^(5h) are CF₃.

In some embodiments of Formula IIc, v is 1 and R^(5h) is OMe.

In some embodiments of Formula IIc, v is 2 and both R^(5h) are OMe.

In some embodiments of Formula IIc, v is 2 and one R^(5h) is F and theother R^(5h) is OMe.

In some embodiments of Formula IIc, v is 2 and one R^(5h) is F and theother R^(5h) is CF₃.

In some embodiments of Formula IIc, v is 2 and one R^(5h) is F and theother R^(5h) is OMe.

In some embodiments of Formula IIc, v is 1 and R^(5h) is CN.

In some embodiments of Formula IIc, v is 2 and both R^(5h) are CN.

In some embodiments of Formula IIc, v is 2 and one R^(5h) is F and theother R^(5h) is CN.

In some embodiments of Formula IIc, w is 1.

In some embodiments of Formula IIc, w is 2.

In some embodiments of Formula IIc, w is 1 and R^(5i) is F.

In some embodiments of Formula IIc, w is 2 and both R^(5i) are F.

In some embodiments of Formula IIc, w is 1 and R^(5i) is Me.

In some embodiments of Formula IIc, w is 2 and both R^(5i) are Me.

In some embodiments of Formula IIc, w is 1 and R^(5i) is CF₃.

In some embodiments of Formula IIc, w is 2 and both R^(5i) are CF₃.

In some embodiments of Formula IIc, w is 1 and R^(5i) is OMe.

In some embodiments of Formula IIc, w is 2 and both R^(5i) are OMe.

In some embodiments of Formula IIc, w is 2 and one R^(5i) is F and theother R^(5i) is OMe.

In some embodiments of Formula IIc, w is 2 and one R^(5i) is F and theother R^(5i) is CF₃.

In some embodiments of Formula IIc, w is 2 and one R^(5i) is F and theother R^(5i) is OMe.

In some embodiments of Formula IIc, w is 1 and R^(5i) is CN.

In some embodiments of Formula IIc, w is 2 and both R^(5i) are CN.

In some embodiments of Formula IIc, w is 2 and one R^(5i) is F and theother R^(5i) is CN.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is —CH₂OH.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h)or R^(5i) is —CH₂N(R^(3b))₂.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h)or R^(5i) is —CH₂NH₂.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h)or R^(5i) is —CH₂NHMe.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h)or R^(5i) is —CH₂NMe₂.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h)or R^(5i) is —CH₂NHEt.

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is —CH₂N(Me)(Et).

In some embodiments of Formula IIc, at least one R^(5f), R^(5g), R^(5h),or R^(5i) is —CH₂NEt₂.

Some embodiments of Formula II include compounds of Formula (IId):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IId, Ring C is

In some embodiments of Formula IId, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IId, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR⁶, and CN.

In some embodiments of Formula IId, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR⁶,and CN.

In some embodiments of Formula IId, R^(5a) is a substituent attached tothe ring and is selected from the group consisting of unsubstituted—C₂₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR′, andCN; j is 1

In some embodiments of Formula IId, R^(5b) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR′, and CN; k is 1 to 4.

In some embodiments of Formula IId, R^(5b) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, halide, —OR′, and CN; k is 0 to 4.

In some embodiments of Formula IId, R^(5c) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₂₋₅ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, halide, —OR⁶, and CN; x is 1 to 3.

In some embodiments of Formula IId, R^(5d) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, and CN; z is 1 or 2.

In some embodiments of Formula IId, R^(5d) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, halide, —OR⁶, and CN; z is 0 to 2.

In some embodiments of Formula IId, R^(5e) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of H, H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, and CN; s is 1 to 4.

In some embodiments of Formula IId, R^(5e) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, and CN; s is 0 to 4.

In some embodiments of Formula IId, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, and —C₁₋₃haloalkyl.

In some embodiments of Formula IId, each R^(6a) is independentlyselected from the group consisting of unsubstituted —C₂₋₆ alkyl and—C₁₋₃ haloalkyl.

In some embodiments of Formula IId, each R^(6b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IId, each J is independently N or C.

In some embodiments of Formula IId, at least one J must be N and atleast one J must be C.

In some embodiments of Formula IId, each U is independently N or C.

In some embodiments of Formula IId, at least one U must be C.

In some embodiments of Formula IId, p is 1 to 3.

In some embodiments of Formula IId, p is 0 to 3.

In some embodiments of Formula IId, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IId, k is 0.

Some embodiments of Formula II include compounds of Formula (He):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIe, Ring C is wherein a carbon atom onthe ring is attached to the carbonyl carbon.

In some embodiments of Formula IIe, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIe, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR⁶, and CN.

In some embodiments of Formula IIe, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR⁶,and CN.

In some embodiments of Formula IIe, R^(5a) is one substituent attachedto the para position of phenyl and is selected from the group consistingof H, unsubstituted C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl,F, Br, I, —OR⁶, and CN.

In some embodiments of Formula IIe, R^(5b) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, and CN; k is 1 to 4.

In some embodiments of Formula IIe, R^(5b) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, halide, —OR⁶, and CN; k is 0 to 4.

In some embodiments of Formula IIe, R^(5c) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₂₋₅ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, halide, —OR⁶, and CN; x is 1 to 4.

In some embodiments of Formula IIe, R^(5d) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR′, and CN; z is 1 or 2.

In some embodiments of Formula IIe, R^(5d) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, halide, —OR′, and CN; z is 0 to 2.

In some embodiments of Formula IIe, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, and —C₁₋₃haloalkyl.

In some embodiments of Formula IIe, each R^(6a) is independentlyselected from the group consisting of unsubstituted —C₁₋₆ alkyl and—C₁₋₃ haloalkyl.

In some embodiments of Formula IIe, each R^(6b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIe, each A is independently N or C.

In some embodiments of Formula IIe, at least one A must be C.

In some embodiments of Formula IIe, each U is independently N or C.

In some embodiments of Formula IIe, at least one U must be N and atleast one U must be C.

In some embodiments of Formula IIe, p is 0 to 4.

In some embodiments of Formula IIe, p is 1 to 4.

In some embodiments of Formula IIe, Ring C is selected from the groupconsisting of

In some embodiments of Formula IIe, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIe, R^(5a) is a OMe.

In some embodiments of Formula IIe, R^(5a) is a halide.

In some embodiments of Formula IIe, R^(5a) is a F.

In some embodiments of Formula IIe, R^(5a) is a Me.

In some embodiments of Formula IIe, R^(5a) is a OH.

In some embodiments of Formula IIe, R^(5a) is a CF₃.

In some embodiments of Formula IIe, R^(5a) is a CN.

In some embodiments of Formula IIe, R^(5a) is a —C₁₋₂ alkyl.

In some embodiments of Formula IIe, R^(5a) is a —C₁₋₃ alkyl.

In some embodiments of Formula IIe, R^(5a) is a —C₁₋₄ alkyl.

In some embodiments of Formula IIe, R^(5a) is a —C₁₋₅ alkyl.

In some embodiments of Formula IIe, R^(5a) is a —C₁₋₆ alkyl.

In some embodiments of Formula IIe, R^(5a) is a —C₂₋₆ alkyl.

In some embodiments of Formula IIe, R^(5a) is a —C₃₋₆ alkyl.

In some embodiments of Formula IIe, R^(5a) is a —C₄₋₆ alkyl.

In some embodiments of Formula IIe, R^(5a) is a —C₂₋₅ alkyl.

In some embodiments of Formula IIe, R^(5a) is a —C₃₋₅ alkyl.

In some embodiments of Formula IId and IIe, z is 0.

Some embodiments of Formula II include compounds of Formula (IIf):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIf, Ring C is

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIf, Ring D is selected from the groupconsisting of

and a 5-membered heteroaryl(R^(5b))_(k), wherein a carbon atom on thering is attached to the carbonyl carbon.

In some embodiments of Formula IIf, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR⁶, and CN.

In some embodiments of Formula IIf, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR⁶,and CN.

In some embodiments of Formula IIf, R^(5a) is a substituent attached tophenyl and is selected from the group consisting of H, unsubstituted—C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR^(6a),and CN; j is 1 to 5

In some embodiments of Formula IIf, R^(5a) is a substituent attached tophenyl and is selected from the group consisting of unsubstituted —C₁₋₆alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR′, and CN; jis 0 to 5

In some embodiments of Formula IIf, R^(5b) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, and CN; k is 1 to 4.

In some embodiments of Formula IIf, R^(5b) is a substituent attached tothe ring and is independently selected at each occurrence from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃haloalkyl, halide, —OR⁶, and CN; k is 0 to 4.

In some embodiments of Formula IIf, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, and —C₁₋₃haloalkyl.

In some embodiments of Formula IIf, each R^(6a) is independentlyselected from the group consisting of unsubstituted —C₂₋₆ alkyl and—C₁₋₃ haloalkyl.

In some embodiments of Formula IIf, each R^(6b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIf, each A is independently N or C.

In some embodiments of Formula IIf, at least one A must be N and atleast one A must be C.

In some embodiments of Formula IIf, Q is S or 0.

In some embodiments of Formula IIf, p is 0 to 4.

In some embodiments of Formula IIf, p is 1 to 4.

In some embodiments of Formula IIf, Ring C is selected from the groupconsisting of

In some embodiments of Formula IIf, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula He and IIf, k is 0.

In some embodiments of Formula II, IIa, IIc, IId, IIe, and IIf, each R⁴is independently selected from the group consisting of F, Cl, Me, OMe,OH, CF₃ and CN; and p is 0 to 2.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf,—C₁₋₃ haloalkyl is CF₃.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, pis 0.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is a halide.

In some embodiments of Formula II, IIa, lib, IIc, IId, IIe, and IIf, atleast one R⁴ is F.

In some embodiments of Formula II, IIa, lib, IIc, IId, IIe, and IIf, atleast one R⁴ is Cl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is Me.

In some embodiments of Formula II, IIa, IIc, IId, IIe, and IIf, at leastone R⁴ is OH.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is OMe.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is CF₃.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is CN.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, pis 0-3.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, pis 0-2.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, pis 2.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, pis 1.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, R⁴is F; and p is 1.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, R⁴is F; and p is 2.

In some embodiments of Formula II, IIa, IIc, IId, IIe, and IIf, R⁴ isOH; and p is 1.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, R⁴is OMe; and p is 1-2.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is —C₁₋₂ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is —C₁₋₃ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is —C₁₋₄ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is —C₁₋₅ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is —C₁₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is —C₂₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is —C₃₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is —C₄₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is —C₂₋₅ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, atleast one R⁴ is —C₃₋₅ alkyl.

In some embodiments of Formula IIa, IIc, IId, IIe, and IIf, at least oneR^(5a) or R^(5b) is —CH₂OH.

In some embodiments of Formula IIa, IIc, IId, IIe, and IIf, at least oneR^(5a) or R^(5b) is —CH₂N(R^(3b))₂.

In some embodiments of Formula IIa, IIc, IId, IIe, and IIf, at least oneR^(5a) or R^(5b) is —CH₂NH₂.

In some embodiments of Formula IIa, IIc, IId, IIe, and IIf, at least oneR^(5a) or R^(5b) is —CH₂NHMe.

In some embodiments of Formula IIa, IIc, IId, IIe, and IIf, at least oneR^(5a) or R^(5b) is —CH₂NMe₂.

In some embodiments of Formula IIa, IIc, IId, IIe, and IIf, at least oneR^(5a) or R^(5b) is —CH₂NHEt.

In some embodiments of Formula IIa, IIc, IId, IIe, and IIf, at least oneR^(5a) or R^(5b) is —CH₂N(Me)(Et).

In some embodiments of Formula IIa, IIc, IId, IIe, and IIf, at least oneR^(5a) or R^(5b) is —CH₂NEt₂.

In some embodiments of Formula IIa, IIc, IId, and IIe, at least oneR^(5c) or R^(5d) is —CH₂OH.

In some embodiments of Formula IIa, IIc, IId, and IIe, at least oneR^(5c) or R^(5d) is —CH₂N(R^(3b))₂.

In some embodiments of Formula IIa, IIc, IId, and IIe, at least oneR^(5c) or R^(5d) is —CH₂NH₂.

In some embodiments of Formula IIa, IIc, IId, and IIe, at least oneR^(5c) or R^(5d) is —CH₂NHMe.

In some embodiments of Formula IIa, IIc, IId, and IIe, at least oneR^(5c) or R^(5d) is —CH₂NMe₂.

In some embodiments of Formula IIa, IIc, IId, and IIe, at least oneR^(5c) or R^(5d) is —CH₂NHEt.

In some embodiments of Formula IIa, IIc, IId, and IIe, at least oneR^(5c) or R^(5d) is —CH₂N(Me)(Et).

In some embodiments of Formula IIa, IIc, IId, and IIe, at least oneR^(5c) or R^(5d) is —CH₂NEt₂.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5e) is—CH₂OH.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5e) is—CH₂N(R^(3b))₂.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5e) is—CH₂NH₂.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5e) is—CH₂NHMe.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5e) is—CH₂NMe₂.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5e) is—CH₂NHEt.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5e) is—CH₂N(Me)(Et).

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5e) is—CH₂NEt₂.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, R⁶is —C₁₋₂ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, R⁶is —C₁₋₃ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, R⁶is —C₁₋₄ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, R⁶is —C₁₋₅ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, R⁶is —C₁₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, R⁶is C₂₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, R⁶is —C₃₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, R⁶is —C₄₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, R⁶is C₂₋₅ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and IIf, R⁶is C₃₋₅ alkyl.

In some embodiments of Formula IIa, IId, and IIf, at least one R^(5a) ishalide.

In some embodiments of Formula IId, IIe, and IIf, at least one R^(5b) ishalide.

In some embodiments of Formula IIa, IId, and IIe, at least one R^(5c) ishalide.

In some embodiments of Formula IIa, IIc, IId, and IIe, at least oneR^(5d) is halide.

In some embodiments of Formula IIa and IId, at least one R^(5e) ishalide.

In some embodiments of Formula IIa, IId, and IIf, at least one R^(5a) isF.

In some embodiments of Formula IIa, IId, IIe, and IIf, at least oneR^(5b) is F.

In some embodiments of Formula IIa, IId, and IIe, at least one R^(5c) isF.

In some embodiments of Formula IIa, IIc, IId, and IIe, at least oneR^(5d) is F.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5e) isF.

In some embodiments of Formula IIa and IId, at least one R^(5a) orR^(5e) is Cl.

In some embodiments of Formula IId, IIe, and IIf, at least one R^(5b) isCl.

In some embodiments of Formula IIa, IId, and IIe, at least one R^(5c) isCl.

In some embodiments of Formula IIa, IIc, IId, IIe, and IIf, at least oneR^(5d) is Cl.

In some embodiments of Formula IIa and IIf, at least one R^(5a) is Me.

In some embodiments of Formula IIa, IId, IIe, and IIf, at least oneR^(5b) is Me.

In some embodiments of Formula IIa, at least one R^(5c) is Me.

In some embodiments of Formula IIa, IIc, and IIf, at least one R^(5d) isMe.

In some embodiments of Formula IIa and IId, at least one R^(5e) is Me.

In some embodiments of Formula IIa, at least one R^(5a) is OH.

In some embodiments of Formula IIa, IIe, and IIf, at least one R^(5b) isOH.

In some embodiments of Formula IIa, IId, and IIe, at least one R^(5c) isOH.

In some embodiments of Formula IIa and IId, at least one R^(5d) is OH.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5e) isOH.

In some embodiments of Formula He and IIf, at least one R^(5b) is OMe.

In some embodiments of Formula IIa, IId, and IIe, at least one R^(5c) orR^(5d) is OMe.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5e) isOMe.

In some embodiments of Formula IIa, IId, and IIf, at least one R^(5a) isCF₃.

In some embodiments of Formula IIa, IId, IIe, and IIf, at least oneR^(5b) is CF₃.

In some embodiments of Formula IIa, IId, and IIe, at least one R^(5c) isCF₃.

In some embodiments of Formula IIa, IIc, IId, and IIe, at least oneR^(5d) is CF₃.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5e) isCF₃.

In some embodiments of Formula IIa, IId, and IIf, at least one R^(5a) isCN.

In some embodiments of Formula IIa, IId, IIe, and IIf, at least oneR^(5b) is CN.

In some embodiments of Formula IIa, IId, and IIe, at least one R^(5c) isCN.

In some embodiments of Formula IIa, IIc, IId, and IIe, at least oneR^(5d) is CN.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5e) isCN.

In some embodiments of Formula IIa and IIf, at least one R^(5a) is —C₁₋₂alkyl.

In some embodiments of Formula IIa and IIf, at least one R^(5a) is —C₁₋₃alkyl.

In some embodiments of Formula IIa and IIf, at least one R^(5a) is —C₁₋₄alkyl.

In some embodiments of Formula IIa and IIf, at least one R^(5a) is —C₁₋₅alkyl.

In some embodiments of Formula IIa and IIf, at least one R^(5a) is —C₁₋₆alkyl.

In some embodiments of Formula IIa, IId, IIe, and IIf, at least oneR^(5a), R^(5b), R^(5c), R^(5d), or R^(5e) is —C₂₋₆ alkyl.

In some embodiments of Formula IIa, IId, IIe, and IIf, at least oneR^(5a), R^(5b), R^(5c), R^(5d), or R^(5e) is —C₃₋₆ alkyl.

In some embodiments of Formula IIa, IId, IIe, and IIf, at least oneR^(5a), R^(5b), R^(5c), R^(5d), or R^(5e) is —C₄₋₆ alkyl.

In some embodiments of Formula IIa, IId, IIe, and IIf, at least oneR^(5a), R^(5b), R^(5c), R^(5d), or R^(5e) is —C₂₋₅ alkyl.

In some embodiments of Formula IIa, IId, IIe, and IIf, at least oneR^(5a), R^(5b), R^(5c), R^(5d), or R^(5e) is —C₃₋₅ alkyl.

In some embodiments of Formula IIa, IId, IIe, and IIf, at least oneR^(5b) is —C₁₋₃ alkyl.

In some embodiments of Formula IIa, IId, IIe, and IIf, at least oneR^(5b) is —C₁₋₄ alkyl.

In some embodiments of Formula IIa, IId, IIe, and IIf, at least oneR^(5b) is —C₁₋₅ alkyl.

In some embodiments of Formula IIa, IId, IIe, and IIf, at least oneR^(5b) is —C₁₋₆ alkyl.

In some embodiments of Formula IIa, at least one R^(5c) is —C₁₋₃ alkyl.

In some embodiments of Formula IIa, at least one R^(5c) is —C₁₋₄ alkyl.

In some embodiments of Formula IIa, at least one R^(5c) is —C₁₋₅ alkyl.

In some embodiments of Formula IIa, at least one R^(5c) is —C₁₋₆ alkyl.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5d) is—C₁₋₃ alkyl.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5d) is—C₁₋₄ alkyl.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5d) is—C₁₋₅ alkyl.

In some embodiments of Formula IIa, IIc, and IId, at least one R^(5d) is—C₁₋₆ alkyl.

In some embodiments of Formula IIa and IId, at least one R^(5e) is —C₁₋₃alkyl.

In some embodiments of Formula IIa and IId, at least one R^(5e) is —C₁₋₄alkyl.

In some embodiments of Formula IIa and IId, at least one R^(5e) is —C₁₋₅alkyl.

In some embodiments of Formula IIa and IId, at least one R^(5e) is —C₁₋₆alkyl.

In some embodiments of Formula IIa, IId, and IIf, j is 1 and R^(5a) isF.

In some embodiments of Formula IIa, IId, and IIf, j is 2 and both R^(5a)are F.

In some embodiments of Formula IIa and IIf, j is 1 and R^(5a) is Me.

In some embodiments of Formula IIa and IIf, j is 2 and both R^(5a) areMe.

In some embodiments of Formula IIa, IId, and IIf, j is 1 and R^(5a) isCF₃.

In some embodiments of Formula IIa, IId, and IIf, j is 2 and both R^(5a)are CF₃.

In some embodiments of Formula IIa and IIf, j is 2 and one R^(5a) is Fand the other R^(5a) is Me.

In some embodiments of Formula IIa, IId, and IIf, j is 2 and one R^(5a)is F and the other R^(5a) is CF₃.

In some embodiments of Formula IIa, IId, and IIf, j is 1 and R^(5a) isCN.

In some embodiments of Formula IIa, IId, and IIf, j is 2 and both R^(5a)are CN.

In some embodiments of Formula IIa, IId, and IIf, j is 2 and one R^(5a)is F and the other R^(5a) is CN.

In some embodiments of Formula IIa, IId, IIe, and IIf, k is 1 and R^(5b)is F.

In some embodiments of Formula IIa, IId, IIe, and IIf, k is 2 and bothR^(5b) are F.

In some embodiments of Formula IIa, IId, IIe, and IIf, k is 1 and R^(5b)is Me.

In some embodiments of Formula IIa, IId, IIe, and IIf, k is 2 and bothR^(5b) are Me.

In some embodiments of Formula IIa, IId, IIe, and IIf, k is 1 and R^(5b)is CF₃.

In some embodiments of Formula IIa, IId, IIe, and IIf, k is 2 and bothR^(5b) are CF₃.

In some embodiments of Formula IIa, IId, IIe, and IIf, k is 2 and oneR^(5b) is F and the other R^(5b) is Me.

In some embodiments of Formula IIa, IId, IIe, and IIf, k is 2 and oneR^(5b) is F and the other R^(5b) is CF₃.

In some embodiments of Formula IIa, IId, IIe, and IIf, k is 1 and R^(5b)is CN.

In some embodiments of Formula IIa, IId, IIe, and IIf, k is 2 and bothR^(5b) are CN.

In some embodiments of Formula IIa, IId, IIe, and IIf, k is 2 and oneR^(5b) is F and the other R^(5b) is CN.

In some embodiments of Formula IIa, IId, and IIe, x is 1 and R^(5c) isF.

In some embodiments of Formula IIa, IId, and IIe, x is 2 and both R^(5c)are F.

In some embodiments of Formula IIa, x is 1 and R^(5c) is Me.

In some embodiments of Formula IIa, x is 2 and both R^(5c) are Me.

In some embodiments of Formula IIa, IId, and IIe, x is 1 and R^(5c) isCF₃.

In some embodiments of Formula IIa, IId, and IIe, x is 2 and both R^(5c)are CF₃.

In some embodiments of Formula IIa, IId, and IIe, x is 1 and R^(5c) isOMe.

In some embodiments of Formula IIa, IId, and IIe, x is 2 and both R^(5c)are OMe.

In some embodiments of Formula IIa, x is 2 and one R^(5c) is F and theother R^(5c) is Me.

In some embodiments of Formula IIa, IId, and IIe, x is 2 and one R^(5c)is F and the other R^(5c) is CF₃.

In some embodiments of Formula IIa, IId, and IIe, x is 2 and one R^(5c)is F and the other R^(5c) is OMe.

In some embodiments of Formula IIa, IId, and IIe, x is 1 and R^(5c) isCN.

In some embodiments of Formula IIa, IId, and IIe, x is 2 and both R^(5c)are CN.

In some embodiments of Formula IIa, IId, and IIe, x is 2 and one R^(5c)is F and the other R^(5c) is CN.

In some embodiments of Formula IIa, IIc, IId, and IIe, z is 1 and R^(5d)is F.

In some embodiments of Formula IIa, IIc, IId, and IIe, z is 2 and bothR^(5d) are F.

In some embodiments of Formula IIa, IIc, and IIf, z is 1 and R^(5d) isMe.

In some embodiments of Formula IIa, IIc, and IIf, z is 2 and both R^(5d)are Me.

In some embodiments of Formula IIa, IIc, IId, and IIe, z is 1 and R^(5d)is CF₃.

In some embodiments of Formula IIa, IIc, IId, and IIe, z is 2 and bothR^(5d) are CF₃.

In some embodiments of Formula IIa, IId, and IIe, z is 1 and R^(5d) isOMe.

In some embodiments of Formula IIa, IId, and IIe, z is 2 and both R^(5d)are OMe.

In some embodiments of Formula IIa and IIc, z is 2 and one R^(5d) is Fand the other R^(5d) is Me.

In some embodiments of Formula IIa, IIc, IId, and IIe, z is 2 and oneR^(5d) is F and the other R^(5d) is CF₃.

In some embodiments of Formula IIa, IId, and IIe, z is 2 and one R^(5d)is F and the other R^(5d) is OMe.

In some embodiments of Formula IIa, IIc, IId, and IIe, z is 1 and R^(5d)is CN.

In some embodiments of Formula IIa, IIc, IId, and IIe, z is 2 and bothR^(5d) are CN.

In some embodiments of Formula IIa, IIc, IId, and IIe, z is 2 and oneR^(5d) is F and the other R^(5d) is CN.

In some embodiments of Formula IIa and IId, s is 0.

In some embodiments of Formula IIa and IId, s is 1.

In some embodiments of Formula IIa and IId, s is 2.

In some embodiments of Formula IIa, IIc, and IId, s is 1 and R^(5e) isF.

In some embodiments of Formula IIa, IIc, and IId, s is 2 and both R^(5c)are F.

In some embodiments of Formula IIa and IId, s is 1 and R^(5e) is Me.

In some embodiments of Formula IIa and IId, s is 2 and both R^(5e) areMe.

In some embodiments of Formula IIa, IIc, and IId, s is 1 and R^(5e) isCF₃.

In some embodiments of Formula IIa, IIc, and IId, s is 2 and both R^(5c)are CF₃.

In some embodiments of Formula IIa, IIc, and IId, s is 1 and R^(5e) isOMe.

In some embodiments of Formula IIa, IIc, and IId, s is 2 and both R^(5e)are OMe.

In some embodiments of Formula IIa and IId, s is 2 and one R^(5e) is Fand the other R^(5e) is Me.

In some embodiments of Formula IIa, IIc, and IId, s is 2 and one R^(5e)is F and the other R^(5e) is CF₃.

In some embodiments of Formula IIa, IIc, and IId, s is 2 and one R^(5e)is F and the other R^(5e) is OMe.

In some embodiments of Formula IIa, IIc, and IId, s is 1 and R^(5e) isCN.

In some embodiments of Formula IIa, IIc, and IId, s is 2 and both R^(5e)are CN.

In some embodiments of Formula IIa, IIc, and IId, s is 2 and one R^(5e)is F and the other R^(5e) is CN.

Some embodiments of the present disclosure include compounds of Formula(III):

or salts, dermatologically acceptable salts or prodrugs thereof.

In some embodiments of Formula III, each R⁷ is a substituent attached tothe phenyl ring and is independently selected at each occurrence fromthe group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(9a))₂, —C₁₋₃ haloalkyl, halide, —OR⁹, and CN.

In some embodiments of Formula III, each R⁸ is a substituent attached tothe phenyl ring and is independently selected at each occurrence fromthe group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(9a))₂, —C₁₋₃ haloalkyl, halide, —OR⁹, and CN.

In some embodiments of Formula III, each R⁸ is a substituent attached tothe phenyl ring and is independently selected at each occurrence fromthe group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(9a))₂, —C₁₋₃ haloalkyl, halide, —OR⁹, and CN.

In some embodiments of Formula III, each R⁹ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, and —C₁₋₃haloalkyl.

In some embodiments of Formula III, each R^(9a) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula III, each q is 1 to 5.

In some embodiments of Formula III, each R⁷ is independently selectedfrom the group consisting of F, Cl, Me, OMe, OH, CF₃ and CN.

In some embodiments of Formula III, at least one R⁷ is halide.

In some embodiments of Formula III, at least one R⁷ is F.

In some embodiments of Formula III, at least one R⁷ is Cl.

In some embodiments of Formula III, at least one R⁷ is Me.

In some embodiments of Formula III, at least one R⁷ is OH.

In some embodiments of Formula III, at least one R⁷ is OMe.

In some embodiments of Formula III, at least one R⁷ is CF₃.

In some embodiments of Formula III, at least one R⁷ is CN.

In some embodiments of Formula III, q is 1 to 4.

In some embodiments of Formula III, q is 1 to 3.

In some embodiments of Formula III, q is 1 or 2.

In some embodiments of Formula III, q is 2.

In some embodiments of Formula III, q is 1.

In some embodiments of Formula III, q is 1 and R⁷ is F.

In some embodiments of Formula III, q is 2 and both R⁷ are F.

In some embodiments of Formula III, q is 1 and R⁷ is Me.

In some embodiments of Formula III, q is 2 and both R⁷ are Me.

In some embodiments of Formula III, q is 1 and R⁷ is CF₃.

In some embodiments of Formula III, q is 2 and both R⁷ are CF₃.

In some embodiments of Formula III, q is 1 and R⁷ is OMe.

In some embodiments of Formula III, q is 2 and both R⁷ are OMe.

In some embodiments of Formula III, q is 2 and one R⁷ is F and the otherR⁷ is Me.

In some embodiments of Formula III, q is 2 and one R⁷ is F and the otherR⁷ is CF₃.

In some embodiments of Formula III, q is 2 and one R⁷ is F and the otherR⁷ is OMe.

In some embodiments of Formula III, q is 1 and R⁷ is CN.

In some embodiments of Formula III, q is 2 and both R⁷ are CN.

In some embodiments of Formula III, q is 2 and one R⁷ is F and the otherR⁷ is CN.

In some embodiments of Formula III, at least one R⁷ is —C₁₋₂ alkyl.

In some embodiments of Formula III, at least one R⁷ is —C₁₋₃ alkyl.

In some embodiments of Formula III, at least one R⁷ is —C₁₋₄ alkyl.

In some embodiments of Formula III, at least one R⁷ is —C₁₋₅ alkyl.

In some embodiments of Formula III, at least one R⁷ is —C₁₋₆ alkyl.

In some embodiments of Formula III, at least one R⁷ is —C₂₋₆ alkyl.

In some embodiments of Formula III, at least one R⁷ is —C₃₋₆ alkyl.

In some embodiments of Formula III, at least one R⁷ is —C₄₋₆ alkyl.

In some embodiments of Formula III, at least one R⁷ is —C₂₋₅ alkyl.

In some embodiments of Formula III, at least one R⁷ is —C₃₋₅ alkyl.

In some embodiments of Formula III, at least one R⁸ is independentlyselected from the group consisting of H, F, Cl, Me, OMe, OH, CF₃ and CN.

In some embodiments of Formula III, at least one R⁸ is halide.

In some embodiments of Formula III, at least one R⁸ is F.

In some embodiments of Formula III, at least one R⁸ is Cl.

In some embodiments of Formula III, at least one R⁸ is Me.

In some embodiments of Formula III, at least one R⁸ is OH.

In some embodiments of Formula III, at least one R⁸ is OMe.

In some embodiments of Formula III, at least one R⁸ is CF₃.

In some embodiments of Formula III, at least one R⁸ is CN.

In some embodiments of Formula III, p is 0 to 4.

In some embodiments of Formula III, p is 0 to 3.

In some embodiments of Formula III, p is 0 to 2.

In some embodiments of Formula III, p is 1 to 4.

In some embodiments of Formula III, p is 1 to 3.

In some embodiments of Formula III, p is 1 or 2.

In some embodiments of Formula III, p is 2.

In some embodiments of Formula III, p is 1.

In some embodiments of Formula III, p is 0.

In some embodiments of Formula III, p is 1 and R⁸ is F.

In some embodiments of Formula III, p is 2 and both R⁸ are F.

In some embodiments of Formula III, p is 1 and R⁸ is Me.

In some embodiments of Formula III, p is 2 and both R⁸ are Me.

In some embodiments of Formula III, p is 1 and R⁸ is CF₃.

In some embodiments of Formula III, p is 2 and both R⁸ are CF₃.

In some embodiments of Formula III, p is 1 and R⁸ is OMe.

In some embodiments of Formula III, p is 2 and both R⁸ are OMe.

In some embodiments of Formula III, p is 2 and one R⁸ is F and the otherR⁸ is Me.

In some embodiments of Formula III, p is 2 and one R⁸ is F and the otherR⁸ is CF₃.

In some embodiments of Formula III, p is 2 and one R⁸ is F and the otherR⁸ is OMe.

In some embodiments of Formula III, p is 1 and R⁸ is CN.

In some embodiments of Formula III, p is 2 and both R⁸ are CN.

In some embodiments of Formula III, p is 2 and one R⁸ is F and the otherR⁸ is CN.

In some embodiments of Formula III, at least one R⁸ is —C₁₋₂ alkyl.

In some embodiments of Formula III, at least one R⁸ is —C₁₋₃ alkyl.

In some embodiments of Formula III, at least one R⁸ is —C₁₋₄ alkyl.

In some embodiments of Formula III, at least one R⁸ is —C₁₋₅ alkyl.

In some embodiments of Formula III, at least one R⁸ is —C₁₋₆ alkyl.

In some embodiments of Formula III, at least one R⁸ is —C₂₋₆ alkyl.

In some embodiments of Formula III, at least one R⁸ is —C₃₋₆ alkyl.

In some embodiments of Formula III, at least one R⁸ is —C₄₋₆ alkyl.

In some embodiments of Formula III, at least one R⁸ is —C₂₋₅ alkyl.

In some embodiments of Formula III, at least one R⁸ is —C₃₋₅ alkyl.

In some embodiments of Formula III, R⁹ is —C₁₋₂ alkyl.

In some embodiments of Formula III, R⁹ is —C₁₋₃ alkyl.

In some embodiments of Formula III, R⁹ is —C₁₋₄ alkyl.

In some embodiments of Formula III, R⁹ is —C₁₋₅ alkyl.

In some embodiments of Formula III, R⁹ is —C₁₋₆ alkyl.

In some embodiments of Formula III, R⁹ is —C₂₋₆ alkyl.

In some embodiments of Formula III, R⁹ is —C₃₋₆ alkyl.

In some embodiments of Formula III, R⁹ is —C₄₋₆ alkyl.

In some embodiments of Formula III, R⁹ is —C₂₋₅ alkyl.

In some embodiments of Formula III, R⁹ is —C₃₋₅ alkyl.

In some embodiments of Formula III, at least one R⁷ and/or R⁸ is —CH₂OH.

In some embodiments of Formula III, at least one R⁷ and/or R⁸ is—CH₂N(R^(9a))₂.

In some embodiments of Formula III, at least one R⁷ and/or R⁸ is—CH₂NH₂.

In some embodiments of Formula III, at least one R⁷ and/or R⁸ is—CH₂NHMe.

In some embodiments of Formula III, at least one R⁷ and/or R⁸ is—CH₂NMe₂.

In some embodiments of Formula III, at least one R⁷ and/or R⁸ is—CH₂NHEt.

In some embodiments of Formula III, at least one R⁷ and/or R⁸ is—CH₂N(Me)(Et).

In some embodiments of Formula III, at least one R⁷ and/or R⁸ is—CH₂NEt₂.

Some embodiments of Formula III include compounds of Formula (IIIa):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIIa, R¹⁰ is one substituent attached tothe ortho position of phenyl and is selected from the group consistingof H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR¹³, and CN.

In some embodiments of Formula IIIa, R¹¹ is one substituent attached tothe ortho position of phenyl and is selected from the group consistingof unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl,halide, —OR¹³, and CN.

In some embodiments of Formula IIIa, each R¹² is a substituent attachedto the phenyl ring and is independently selected at each occurrence fromthe group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl, halide, —OR¹³, and CN.

In some embodiments of Formula IIIa, each R¹² is a substituent attachedto the phenyl ring and is independently selected at each occurrence fromthe group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl, halide, —OR¹³, and CN.

In some embodiments of Formula IIIa, each R¹³ is independently selectedfrom the group consisting of unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula IIIa, each R^(13b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIIa, q is 0 to 5.

In some embodiments of Formula IIIa, q is 1 to 5.

In some embodiments of Formula ilia, at least one R¹² is selected fromthe group consisting of H, F, Cl, Me, OMe, CF₃, and CN.

In some embodiments of Formula IIIa, q is 0.

In some embodiments of Formula IIIa, at least one R¹² is a halide.

In some embodiments of Formula IIIa, at least one R¹² is F.

In some embodiments of Formula IIIa, at least one R¹² is Cl.

In some embodiments of Formula IIIa, at least one R¹² is Me.

In some embodiments of Formula IIIa, at least one R¹² is OH.

In some embodiments of Formula IIIa, at least one R¹² is OMe.

In some embodiments of Formula IIIa, at least one R¹² is CF₃.

In some embodiments of Formula IIIa, at least one R¹² is CN.

In some embodiments of Formula IIIa, q is 1 and R¹² is F.

In some embodiments of Formula IIIa, q is 2 and both R¹² are F.

In some embodiments of Formula IIIa, q is 1 and R¹² is Me.

In some embodiments of Formula IIIa, q is 2 and both R¹² are Me.

In some embodiments of Formula IIIa, q is 1 and R¹² is CF₃.

In some embodiments of Formula IIIa, q is 2 and both R¹² are CF₃.

In some embodiments of Formula IIIa, q is 1 and R¹² is OMe.

In some embodiments of Formula IIIa, q is 2 and both R¹² are OMe.

In some embodiments of Formula ilia, q is 2 and one R¹² is F and theother R¹² is Me.

In some embodiments of Formula ilia, q is 2 and one R¹² is F and theother R¹² is CF₃.

In some embodiments of Formula ilia, q is 2 and one R¹² is F and theother R¹² is OMe.

In some embodiments of Formula IIIa, q is 1 and R¹² is CN.

In some embodiments of Formula IIIa, q is 2 and both R¹² are CN.

In some embodiments of Formula ilia, q is 2 and one R¹² is F and theother R¹² is CN.

In some embodiments of Formula IIIa, q is 1 and R¹² is F or Cl.

In some embodiments of Formula IIIa, at least one R¹² is —C₁₋₂ alkyl.

In some embodiments of Formula IIIa, at least one R¹² is —C₁₋₃ alkyl.

In some embodiments of Formula IIIa, at least one R¹² is —C₁₋₄ alkyl.

In some embodiments of Formula IIIa, at least one R¹² is —C₁₋₅ alkyl.

In some embodiments of Formula IIIa, at least one R¹² is —C₁₋₆ alkyl.

In some embodiments of Formula IIIa, at least one R¹² is —C₂₋₆ alkyl.

In some embodiments of Formula IIIa, at least one R¹² is —C₃₋₆ alkyl.

In some embodiments of Formula IIIa, at least one R¹² is —C₄₋₆ alkyl.

In some embodiments of Formula IIIa, at least one R¹² is —C₂₋₅ alkyl.

In some embodiments of Formula IIIa, at least one R¹² is —C₃₋₅ alkyl.

Some embodiments of Formula III include compounds of Formula (IIIb).

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIIb, R¹⁴ is selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl and —C₁₋₃ haloalkyl.

In some embodiments of Formula IIIb, R¹⁵ is selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl and —C₁₋₃ haloalkyl.

In some embodiments of Formula IIIb, each R¹⁶ is a substituent attachedto the phenyl ring and is independently selected at each occurrence fromthe group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(17b))₂, —C₁₋₃ haloalkyl, halide, —OR′, and CN.

In some embodiments of Formula IIIb, each R¹⁷ is independently selectedfrom the group consisting of unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula IIIb, each R^(17b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIIb, each q is 0 to 5.

In some embodiments of Formula IIIb, at least one R¹⁶ is selected fromthe group consisting of H, F, Cl, Me, OMe, CF₃, and CN.

In some embodiments of Formula IIIb, q is 0.

In some embodiments of Formula IIIb, at least one R¹⁶ is OH.

In some embodiments of Formula IIIb, at least one R¹⁶ is OMe.

In some embodiments of Formula IIIb, q is 1 and R¹⁶ is F.

In some embodiments of Formula IIIb, q is 2 and both R¹⁶ are F.

In some embodiments of Formula IIIb, q is 1 and R¹⁶ is Me.

In some embodiments of Formula IIIb, q is 2 and both R¹⁶ are Me.

In some embodiments of Formula IIIb, q is 1 and R¹⁶ is CF₃.

In some embodiments of Formula IIIb, q is 2 and both R¹⁶ are CF₃.

In some embodiments of Formula IIIb, q is 1 and R¹⁶ is OMe.

In some embodiments of Formula IIIb, q is 2 and both R¹⁶ are OMe.

In some embodiments of Formula IIIb, q is 2 and one R¹⁶ is F and theother R¹⁶ is Me.

In some embodiments of Formula IIIb, q is 2 and one R¹⁶ is F and theother R¹⁶ is CF₃.

In some embodiments of Formula IIIb, q is 2 and one R¹⁶ is F and theother R¹⁶ is OMe.

In some embodiments of Formula IIIb, q is 1 and R¹⁶ is CN.

In some embodiments of Formula IIIb, q is 2 and both R¹⁶ are CN.

In some embodiments of Formula IIIb, q is 2 and one R¹⁶ is F and theother R¹⁶ is CN.

In some embodiments of Formula IIIb, at least one R¹⁶ is —CH₂OH.

In some embodiments of Formula IIIb, at least one R¹⁶ is—CH₂N(R^(17b))₂.

In some embodiments of Formula IIIb, at least one R¹⁶ is —CH₂NH₂.

In some embodiments of Formula IIIb, at least one R¹⁶ is —CH₂NHMe.

In some embodiments of Formula IIIb, at least one R¹⁶ is —CH₂NMe₂.

In some embodiments of Formula IIIb, at least one R¹⁶ is —CH₂NHEt.

In some embodiments of Formula IIIb, at least one R¹⁶ is —CH₂N(Me)(Et).

In some embodiments of Formula IIIb, at least one R¹⁶ is —CH₂NEt₂.

In some embodiments of Formula IIIb, R¹⁷ is —C₁₋₂ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₁₋₃ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₁₋₄ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₁₋₅ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₁₋₆ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₂₋₆ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₃₋₆ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₄₋₆ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₂₋₅ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₃₋₅ alkyl.

Some embodiments of Formula III include compounds of Formula

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIIc, Ring E is selected from the groupconsisting of

In some embodiments of Formula IIIc, R¹⁰ is one substituent attached tothe ortho position of the phenyl ring and is selected from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR¹³, and CN.

In some embodiments of Formula IIIc, R¹¹ is one substituent attached tothe ortho position of the phenyl ring and is selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(13b))₂, —C₁₋₃haloalkyl, halide, —OR¹³, and CN.

In some embodiments of Formula IIIc, R^(12a) is one substituent attachedto the para position of the phenyl ring and is selected at eachoccurrence from the group consisting of unsubstituted —C₂₋₆ alkyl,—CH₂OH, —CH₂N(R^(13b))₂, —C₂₋₃ haloalkyl, Cl, I, —OEt, and CN.

In some embodiments of Formula IIIc, R^(12b) is one substituent attachedto the meta position of the phenyl ring and is selected at eachoccurrence from the group consisting of unsubstituted —C₂₋₆ alkyl,—CH₂OH, —CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl, iodide, and —OR¹³a.

In some embodiments of Formula IIIc, R^(u)c is one substituent attachedto the ortho position of the phenyl ring and is selected at eachoccurrence from the group consisting of unsubstituted —C₂₋₆ alkyl,—CH₂OH, —CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl, F, I, —OR¹³a, and CN.

In some embodiments of Formula IIIc, R^(12d) is a substituents attachedto the ring and are independently selected at each occurrence from thegroup consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(13b))₂,—C₁₋₃ haloalkyl, F, Br, I, —OR¹³, and CN; k is 2 to 5.

In some embodiments of Formula IIIc, each R¹³ is independently selectedfrom the group consisting of unsubstituted —C₁₋₆ alkyl and —C₁₋₃haloalkyl.

In some embodiments of Formula IIIc, each R^(13a) is independentlyselected from the group consisting of unsubstituted —C₂₋₆ alkyl and—C₁₋₃ haloalkyl.

In some embodiments of Formula IIIc, each R^(13b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIIc, at least one R^(12d) is —C₂₋₆alkyl.

In some embodiments of Formula IIIc, at least one R^(12d) is —C₂₋₅alkyl.

In some embodiments of Formula IIIc, at least one R^(12d) is —C₂₋₄alkyl.

In some embodiments of Formula IIIc, at least one R^(12d) is —C₃₋₆alkyl.

In some embodiments of Formula IIIc, at least one R^(12d) is —C₄₋₆alkyl.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), and/orR^(13a) is —C₂₋₆ alkyl.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), and/orR^(13a) is —C₂₋₅ alkyl.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), and/orR^(13a) is —C₂₋₄ alkyl.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), and/orR^(13a) is —C₃₋₆ alkyl.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), and/orR^(13a) is —C₄₋₆ alkyl.

In some embodiments of Formula IIIc, at least one R^(12d) is Me.

In some embodiments of Formula IIIc, at least one R^(12d) is CF₃.

In some embodiments of Formula IIIc, R^(13a) is Me.

In some embodiments of Formula IIIc, R^(12b), R^(12c), and/or R^(13a) isCF₃.

In some embodiments of Formula IIIc, at least one R^(12d) is F.

In some embodiments of Formula IIIc, R^(12c) is F.

In some embodiments of Formula IIIc, R^(12a) is Cl.

In some embodiments of Formula IIIc, at least one R^(12d) is CN.

In some embodiments of Formula IIIc, at least one R^(12d) is —CH₂OH.

In some embodiments of Formula IIIc, at least one R^(12d) is—CH₂N(R^(13b))₂.

In some embodiments of Formula IIIc, at least one R^(12d) is —CH₂NH₂.

In some embodiments of Formula IIIc, at least one R^(12d) is —CH₂NHMe.

In some embodiments of Formula IIIc, at least one R^(12d) is —CH₂NMe₂.

In some embodiments of Formula IIIc, at least one R^(12d) is —CH₂NHEt.

In some embodiments of Formula IIIc, at least one R^(12d) is—CH₂N(Me)(Et).

In some embodiments of Formula IIIc, R^(12a), R^(12c), or R^(12c) is CN.

In some embodiments of Formula IIIc, R^(12a), R^(12b), or R^(12c) is—CH₂OH.

In some embodiments of Formula IIIc, R^(12a), R^(12b), or R^(12c) is—CH₂N(R^(13b))₂.

In some embodiments of Formula IIIc, R^(12a), R^(12b), or R^(12c) is—CH₂NH₂.

In some embodiments of Formula IIIc, R^(12a), R^(12b), or R^(12c) is—CH₂NHMe.

In some embodiments of Formula IIIc, R^(12a), R^(12b), or R^(12c) is—CH₂NMe₂.

In some embodiments of Formula IIIc, R^(12a), R^(12b), or R^(12c) is—CH₂NHEt.

In some embodiments of Formula IIIc, R^(12a), R^(12b), or R^(12c) is—CH₂N(Me)(Et).

In some embodiments of Formula IIIa and IIIc, R¹¹ is —CH₂NEt₂.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is selected from thegroup consisting of H, F, Cl, Me, OMe, CF₃, and CN.

In some embodiments of Formula IIIa and IIIc, R¹¹ is selected from thegroup consisting of F, Cl, Me, OMe, CF₃, and CN.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is H; and R¹¹ is F.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is H; and R¹¹ is Cl.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is H; and R¹¹ is Me.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is H; and R¹¹ is OMe.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is H; and R¹¹ is CF₃.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is H; and R¹¹ is CN.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is F; and R¹¹ is F.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is F; and R¹¹ is Cl.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is F; and R¹¹ is Me.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is F; and R¹¹ is OMe.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is F; and R¹¹ is CF₃.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is F; and R¹¹ is CN.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is —C₁₋₂ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is —C₁₋₃ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is —C₁₋₄ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is —C₁₋₅ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is —C₁₋₆ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is —C₂₋₆ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is —C₃₋₆ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is —C₄₋₆ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is —C₂₋₅ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹⁰ is —C₃₋₅ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —C₁₋₂ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —C₁₋₃ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —C₁₋₄ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —C₁₋₅ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —C₁₋₆ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —C₂₋₆ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —C₃₋₆ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —C₄₋₆ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —C₂₋₅ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —C₃₋₅ alkyl.

In some embodiments of Formula IIIa and IIIc, q is 1 to 4.

In some embodiments of Formula IIIa and IIIc, q is 1 to 3.

In some embodiments of Formula IIIa, q is 1 or 2.

In some embodiments of Formula IIIa and IIIc, q is 2.

In some embodiments of Formula IIIa and IIIc, q is 1.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —CH₂OH.

In some embodiments of Formula IIIa and IIIc, R¹¹ is a —CH₂N(R^(13b))₂.

In some embodiments of Formula IIIa and IIIc, R¹¹ is a —CH₂NH₂.

In some embodiments of Formula IIIa and IIIc, R¹¹ is a —CH₂NHMe.

In some embodiments of Formula IIIa and IIIc, R¹¹ is a —CH₂NMe₂.

In some embodiments of Formula IIIa and IIIc, R¹¹ is a —CH₂NHEt.

In some embodiments of Formula IIIa and IIIc, R¹¹ is a —CH₂N(Me)(Et).

In some embodiments of Formula IIIa and IIIc, R¹¹ is a —CH₂NEt₂.

In some embodiments of Formula IIIa and IIIc, R¹¹ is a —C₁₋₂ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —C₁₋₃ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —C₁₋₄ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is —C₁₋₅ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is a —C₁₋₆ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is a —C₂₋₆ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is a —C₃₋₆ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹¹ is a —C₄₋₆ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹³ is a —C₂₋₅ alkyl.

In some embodiments of Formula IIIa and IIIc, R¹³ is a —C₃₋₅ alkyl.

Some embodiments of Formula III include compounds of Formula (IIId):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIId, R¹⁴ is selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl and —C₁₋₃ haloalkyl.

In some embodiments of Formula IIId, R¹⁵ is selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl and —C₁₋₃ haloalkyl.

In some embodiments of Formula IIId, each R¹⁶ is a substituent attachedto the phenyl ring and is independently selected at each occurrence fromthe group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(17b))₂, —C₁₋₃ haloalkyl, halide, —OR′, and CN.

In some embodiments of Formula IIId, each R^(17a) is independentlyselected from the group consisting of unsubstituted —C₃₋₆ alkyl and—C₁₋₃ haloalkyl.

In some embodiments of Formula IIId, each R^(17a) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIId, q is 1 to 5.

In some embodiments of Formula IIId, R^(17a) is —C₃₋₆ alkyl.

In some embodiments of Formula IIId, R^(17a) is —C₄₋₆ alkyl.

In some embodiments of Formula IIId, R^(17a) is —C₃₋₅ alkyl.

In some embodiments of Formula IIId, at least one R¹⁶ is —CH₂OH.

In some embodiments of Formula IIId, at least one R¹⁶ is—CH₂N(R^(17b))₂.

In some embodiments of Formula IIId, at least one R¹⁶ is —CH₂NH₂.

In some embodiments of Formula IIId, at least one R¹⁶ is —CH₂NHMe.

In some embodiments of Formula IIId, at least one R¹⁶ is —CH₂NMe₂.

In some embodiments of Formula IIId, at least one R¹⁶ is —CH₂NHEt.

In some embodiments of Formula IIId, at least one R¹⁶ is —CH₂N(Me)(Et).

In some embodiments of Formula IIId, at least one R¹⁶ is —CH₂NEt₂.

In some embodiments of Formula IIIa, IIIb, IIIc, and IIId, —C₁₋₃haloalkyl is —CF₃.

In some embodiments of Formula IIIb and IIId, R¹⁴ is Me

In some embodiments of Formula IIIb and IIId, R¹⁴ is Et.

In some embodiments of Formula IIIb and IIId, R¹⁴ is —C₁₋₂ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁴ is —C₁₋₃ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁴ is —C₁₋₄ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁴ is —C₁₋₅ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁴ is —C₁₋₆ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁴ is —C₂₋₆ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁴ is —C₃₋₆ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁴ is —C₄₋₆ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁴ is —C₂₋₅ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁴ is —C₃₋₅ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁴ is —C₁₋₂ haloalkyl.

In some embodiments of Formula IIIb and IIId, R¹⁴ is —C₁₋₃ haloalkyl.

In some embodiments of Formula IIIb and IIId, R¹⁴ is —C₂₋₃ haloalkyl.

In some embodiments of Formula IIIb and IIId, R¹⁴ is CF₃.

In some embodiments of Formula IIIb and IIId, R¹⁵ is Me

In some embodiments of Formula IIIb and IIId, R¹⁵ is Et.

In some embodiments of Formula IIIb and IIId, R¹⁵ is —C₁₋₂ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁵ is —C₁₋₃ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁵ is —C₁₋₄ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁵ is —C₁₋₅ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁵ is —C₁₋₆ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁵ is —C₂₋₆ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁵ is —C₃₋₆ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁵ is —C₄₋₆ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁵ is —C₂₋₅ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁵ is —C₃₋₅ alkyl.

In some embodiments of Formula IIIb and IIId, R¹⁵ is —C₁₋₂ haloalkyl.

In some embodiments of Formula IIIb and IIId, R¹⁵ is —C₁₋₃ haloalkyl.

In some embodiments of Formula IIIb and IIId, R¹⁵ is —C₂₋₃ haloalkyl.

In some embodiments of Formula IIIb and IIId, R¹⁵ is CF₃.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is ahalide.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is F.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is Cl.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is Me.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is CF₃.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is CN.

In some embodiments of Formula IIIb and IIId, q is 1 to 4.

In some embodiments of Formula IIIb and IIId, q is 1 to 3.

In some embodiments of Formula IIIb and IIId, q is 1 or 2.

In some embodiments of Formula IIIb and IIId, q is 2.

In some embodiments of Formula IIIb and IIId, q is 1.

In some embodiments of Formula IIIb and IIId, q is 1 and R¹⁶ is F or Cl.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is —C₁₋₂alkyl.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is —C₁₋₃alkyl.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is —C₁₋₄alkyl.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is —C₁₋₅alkyl.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is —C₁₋₆alkyl.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is —C₂₋₆alkyl.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is —C₃₋₆alkyl.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is —C₄₋₆alkyl.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is —C₂₋₅alkyl.

In some embodiments of Formula IIIb and IIId, at least one R¹⁶ is —C₃₋₅alkyl.

Some embodiments of the present disclosure include compounds of Formula(IV):

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IV, Ring F is

In some embodiments of Formula IV, Ring G is selected from the groupconsisting of

and a 5-6 membered heteroaryl(R^(19d))_(z), wherein a carbon atom on thering is attached to the carbonyl carbon.

In some embodiments of Formula IV, each R¹⁸ is a substituent attached toRing F and is independently selected at each occurrence from the groupconsisting of H, —C₁₋₃ haloalkyl, halide, —OR²⁰, and CN.

In some embodiments of Formula IV, each R¹⁸ is a substituent attached toRing F and is independently selected at each occurrence from the groupconsisting of —C₁₋₃ haloalkyl, halide, —OR²⁰, and CN.

In some embodiments of Formula IV, R^(19a) is a substituent attached tothe para position of phenyl and is selected from the group consisting ofH, unsubstituted —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, F,Br, I, —OR²⁰, and CN.

In some embodiments of Formula IV, R^(19b) is a substituent attached tothe meta or ortho position of phenyl and is selected from the groupconsisting of H, unsubstituted —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃haloalkyl, halide, —OR²⁰, and CN.

In some embodiments of Formula IV, R^(19c) is a substituent attached tothe phenyl and is independently selected at each occurrence from thegroup consisting of H, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, halide,—OR²⁰, and CN; k is 2 to 5.

In some embodiments of Formula IV, R^(19c) is a substituent attached tothe phenyl and is independently selected at each occurrence from thegroup consisting of —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, halide, —OR²⁰,and CN; k is 0 to 5.

In some embodiments of Formula IV, R^(19d) is a substituent attached tothe heteroaryl ring and is independently selected at each occurrencefrom the group consisting of H, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃haloalkyl,halide, —OR²⁰, and CN; z is 0 to 4.

In some embodiments of Formula IV, R^(19d) is a substituent attached tothe heteroaryl ring and is independently selected at each occurrencefrom the group consisting of —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl,halide, —OR²⁰, and CN; z is 1 to 4.

In some embodiments of Formula IV, each R²⁰ is independently selectedfrom the group consisting of H, unsubstituted —C₃₋₆ alkyl, and —C₁₋₃haloalkyl.

In some embodiments of Formula IV, each R²¹ is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IV, p is 0 to 13.

In some embodiments of Formula IV, p is 1 to 13.

In some embodiments of Formula IV, p is 0.

In some embodiments of Formula IV, r is 1 to 5.

In some embodiments of Formula IV,

is selected from the group consisting of:

In some embodiments of Formula IV,

is selected from the group consisting of:

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) isselected from the group consisting of H, F, Cl, Me, OMe, CF₃, and CN.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) ishalide.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is F.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) isCl.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) isMe.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) isOH.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) isOMe.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) isCF₃.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) isCN.

In some embodiments of Formula IV, R^(19b) is selected from the groupconsisting of H, F, Cl, Me, OMe, CF₃, and CN.

In some embodiments of Formula IV, R^(19a) or R^(19b) is H.

In some embodiments of Formula IV, R^(19a) or R^(19b) is halide.

In some embodiments of Formula IV, R^(19a) or R^(19b) is F.

In some embodiments of Formula IV, R^(19a) or R^(19b) is Cl.

In some embodiments of Formula IV, R^(19a) or R^(19b) is Me.

In some embodiments of Formula IV, R^(19a) or R^(19b) is OH.

In some embodiments of Formula IV, R^(19a) or R^(19b) is OMe.

In some embodiments of Formula IV, R^(19a) or R^(19b) is CF₃.

In some embodiments of Formula IV, R^(19a) or R^(19b) is CN.

In some embodiments of Formula IV, z is 1.

In some embodiments of Formula IV, z is 2.

In some embodiments of Formula IV, z is 2 and both R^(19d) are F.

In some embodiments of Formula IV, z is 2 and both R^(19d) are Me.

In some embodiments of Formula IV, z is 2 and both R^(19d) are CF₃.

In some embodiments of Formula IV, z is 2 and both R^(19d) are OMe.

In some embodiments of Formula IV, z is 2 and one R^(19d) is F and theother R^(19d) is Me.

In some embodiments of Formula IV, z is 2 and one R^(19d) is F and theother R^(19d) is CF₃.

In some embodiments of Formula IV, z is 2 and one R^(19d) is F and theother R^(19d) is OMe.

In some embodiments of Formula IV, z is 2 and both R^(19d) are CN.

In some embodiments of Formula IV, z is 2 and one R^(19d) is F and theother R^(19d) is CN.

In some embodiments of Formula IV, z is 2 and one R^(19d) is F and theother R^(19d) is Cl.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—C₁₋₂ alkyl.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—C₁₋₃ alkyl.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—C₁₋₄ alkyl.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—C₁₋₅ alkyl.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—C₁₋₆ alkyl.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—C₂₋₆ alkyl.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—C₃₋₆ alkyl.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—C₄₋₆ alkyl.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—C₂₋₅ alkyl.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—C₃₋₅ alkyl.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—CH₂OH.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—CH₂N(R^(13b))₂.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—CH₂NH₂.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—CH₂NHMe.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—CH₂NMe₂.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—CH₂NHEt.

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—CH₂N(Me)(Et).

In some embodiments of Formula IV, at least one R^(19c) or R^(19d) is—CH₂NEt₂.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —C₁₋₂ alkyl.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —C₁₋₃ alkyl.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —C₁₋₄ alkyl.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —C₁₋₅ alkyl.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —C₁₋₆ alkyl.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —C₂₋₆ alkyl.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —C₃₋₆ alkyl.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —C₄₋₆ alkyl.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —C₂₋₅ alkyl.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —C₃₋₅ alkyl.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —CH₂OH.

In some embodiments of Formula IV, R^(19a) or R^(19b) is—CH₂N(R^(13b))₂.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —CH₂NH₂.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —CH₂NHMe.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —CH₂NMe₂.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —CH₂NHEt.

In some embodiments of Formula IV, R^(19a) or R^(19b) is —CH₂N(Me)(Et).

In some embodiments of Formula IV, R^(19a) or R^(19b) is —CH₂NEt₂.

In some embodiments of Formula IV,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula IV can form a bond with anyunsubstituted carbon on the Ring G.

In some embodiments of Formula IV,

is selected from the group consisting of:

In some embodiments of Formula IV,

is selected from the group consisting of:

In some embodiments of Formula IV, —C₁₋₃haloalkyl is —CF₃.

Illustrative compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih,Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, andIV are shown in Table 1.

TABLE 1 1

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3

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5

6

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11

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905

The compounds provided herein can be prepared using methods known andunderstood by those of ordinary skill in the art. For example, syntheticmethods such as those described in PCT/US2011/048086 andPCT/US2014/017794 can be used, and both applications are hereinincorporated by reference in their entirety.

The skilled artisan will recognize that some structures described hereincan be resonance forms or tautomers of compounds that can be fairlyrepresented by other chemical structures, even when kinetically, theartisan recognizes that such structures are only a very small portion ofa sample of such compound(s). Such compounds are clearly contemplatedwithin the scope of this disclosure, though such resonance forms ortautomers are not represented herein.

The compounds provided herein may encompass various stereochemicalforms. The compounds also encompass diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds. Separation ofthe individual isomers or selective synthesis of the individual isomersis accomplished by application of various methods which are well knownto practitioners in the art. Unless otherwise indicated, when adisclosed compound is named or depicted by a structure withoutspecifying the stereochemistry and has one or more chiral centers, it isunderstood to represent all possible stereoisomers of the compound.

As used herein, “alkyl” means a branched, or straight chain chemicalgroup containing only carbon and hydrogen, such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl. Alkyl groups can eitherbe unsubstituted or substituted with one or more substituents. Alkylgroups can be saturated or unsaturated (e.g., containing —C═C— or —C≡C—subunits), at one or several positions. Typically, alkyl groups willcomprise 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4carbon atoms, or 1 to 2 carbon atoms).

As used herein, “carbocyclyl” means a cyclic ring system containing onlycarbon atoms in the ring system backbone, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls mayinclude multiple fused rings. Carbocyclyls may have any degree ofsaturation provided that at least one ring in the ring system is notaromatic. Carbocyclyl groups can either be unsubstituted or substitutedwith one or more substituents. Typically, carbocyclyl groups willcomprise 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.

As used herein, “lower alkyl” means a subset of alkyl having 1 to 3carbon atoms, which is linear or branched. Examples of lower alkylsinclude methyl, ethyl, n-propyl and isopropyl. Likewise, radicals usingthe terminology “lower” refer to radicals having 1 to about 3 carbons inthe alkyl portion of the radical.

As used herein, “aryl” means an aromatic ring system containing asingle-ring (e.g., phenyl) or multiple condensed rings (e.g., naphthylor anthryl) with only carbon atoms present in the ring backbone. Arylgroups can either be unsubstituted or substituted with one or moresubstituents. In some embodiments, the aryl is phenyl.

As used herein, “arylalkyl” means an aryl-alkyl-group in which the aryland alkyl moieties are as previously described. In some embodiments,arylalkyl groups contain a C₁₋₄alkyl moiety. Exemplary arylalkyl groupsinclude benzyl and 2-phenethyl.

As used herein, the term “heteroaryl” means a mono-, bi-, tri- orpolycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array;wherein at least one ring in the system is aromatic, and at least onering in the system contains one or more heteroatoms independentlyselected from the group consisting of N, O, and S. Heteroaryl groups caneither be unsubstituted or substituted with one or more substituents.Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl,oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl,isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl,benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl,isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl,pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl,quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, 2,3-dihydrobenzo[b][1,4]oxathiine, and others.

As used herein, “heteroarylalkyl” means a heteroaryl-alkyl-group inwhich the heteroaryl and alkyl moieties are as previously described. Insome embodiments, heteroarylalkyl groups contain a C₁₋₄ alkyl moiety.Exemplary heteroarylalkyl groups include pyridylmethyl.

As used herein, “acyl” means an H—CO— or alkyl-CO—, carbocyclyl-CO—,aryl-CO—, heteroaryl-CO—, or heterocyclyl-CO— group wherein the alkyl,carbocyclyl, aryl or heterocyclyl group is as herein described. In someembodiments, acyls contain a lower alkyl. Exemplary alkyl acyl groupsinclude formyl, acetyl, propanoyl, 2-methylpropanoyl, t-butylacetyl,butanoyl, and palmitoyl.

As used herein, “alkoxycarbonyl” means an alkyl-O—CO— group in which thealkyl group is as described herein. Exemplary alkoxycarbonyl groupsinclude methoxy- and ethoxycarbonyl.

As used herein, “alkoxy” means an alkyl-O— group in which the alkylgroup is as described herein. Exemplary alkoxy groups includedifluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy, hexoxy and heptoxy,and also the linear or branched positional isomers thereof.

As used herein, the terms “halo”, “halide” or “halogen” are usedinterchangeably and mean a chloro, bromo, fluoro, or iodo atom radical.In some embodiments, a halo is a chloro, bromo or fluoro. For example, ahalo can be fluoro.

As used herein, “haloalkyl” means a hydrocarbon substituent, which is alinear or branched or cyclic alkyl, alkenyl or alkynyl substituted withone or more chloro, bromo, fluoro, or iodo atom(s). In some embodiments,a haloalkyl is a fluoroalkyls, wherein one or more of the hydrogen atomshave been substituted by fluoro. In some embodiments, haloalkyls are of1 to about 3 carbons in length (e.g., 1 to about 2 carbons in length or1 carbon in length). The term “haloalkylene” means a diradical variantof haloalkyl, and such diradicals may act as spacers between radicals,other atoms, or between a ring and another functional group.

As used herein, “heterocyclyl” means a nonaromatic cyclic ring systemcomprising at least one heteroatom in the ring system backbone.Heterocyclyls may include multiple fused rings. Heterocyclyls can besubstituted or unsubstituted with one or more substituents. In someembodiments, heterocycles have 5-7 members. In six membered monocyclicheterocycles, the heteroatom(s) are selected from one up to three of O,N or S, and wherein when the heterocycle is five membered, it can haveone or two heteroatoms selected from O, N, or S. Examples ofheterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl,thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl,pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl,thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl,isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl,thiomorpholinyl, and others.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more non-hydrogen atoms of the molecule. It will beunderstood that “substitution” or “substituted with” includes theimplicit proviso that such substitution is in accordance with permittedvalence of the substituted atom and the substituent, and that thesubstitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. Substituents can include, for example,(C₁₋₉ alkyl) optionally substituted with one or more of hydroxyl, —NH₂,—NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂; —(C₁₋₉ haloalkyl); a halide; ahydroxyl; a carbonyl [such as —C(O)OR, and —C(O)R]; a thiocarbonyl [suchas —C(S)OR, —C(O)SR, and —C(S)R]; (C₁₋₉ alkoxyl) optionally substitutedwith one or more of halide, hydroxyl, —NH₂, —NH(C₁₋₃ alkyl), and N(C₁₋₃alkyl)₂; —OPO(OH)₂; a phosphonate [such as —PO(OH)₂ and —PO(OR′)₂];—OPO(OR′)R″; —NRR′; —C(O)NRR′; —C(NR)NR′R″; —C(NR′)R″; a cyano; a nitro;an azido; —SH; —S—R; —OSO₂(OR); a sulfonate [such as —SO₂(OH) and—SO₂(OR)]; —SO₂NR′R″; and —SO₂R; in which each occurrence of R, R′ andR″ are independently selected from H; —(C₁₋₉ alkyl); C₆₋₁₀ aryloptionally substituted with from 1-3 R′″; 5-10 membered heteroarylhaving from 1-4 heteroatoms independently selected from N, O, and S andoptionally substituted with from 1-3 R′″; C₃₋₇ carbocyclyl optionallysubstituted with from 1-3 R′″; and 3-8 membered heterocyclyl having from1-4 heteroatoms independently selected from N, O, and S and optionallysubstituted with from 1-3 R′″; wherein each R′″ is independentlyselected from (C₁₋₆ alkyl), (C₁₋₆ haloalkyl), a halide (e.g., F), ahydroxyl, —C(O)OR, —C(O)R, (C₁₋₆alkoxyl), —NRR′, —C(O)NRR′, and a cyano,in which each occurrence of R and R′ is independently selected from Hand (C₁₋₆ alkyl). In some embodiments, the substituent is selected from(C₁₋₆ alkyl), —(C₁₋₆ haloalkyl), a halide (e.g., F), a hydroxyl,—C(O)OR, —C(O)R, (C₁₋₆ alkoxyl), —NRR′, —C(O)NRR′, and a cyano, in whicheach occurrence of R and R′ is independently selected from H and (C₁₋₆alkyl).

As used herein, when two groups are indicated to be “linked” or “bonded”to form a “ring”, it is to be understood that a bond is formed betweenthe two groups and may involve replacement of a hydrogen atom on one orboth groups with the bond, thereby forming a carbocyclyl, heterocyclyl,aryl, or heteroaryl ring. The skilled artisan will recognize that suchrings can and are readily formed by routine chemical reactions. In someembodiments, such rings have from 3-7 members, for example, 5 or 6members.

“Solvate” refers to the compound formed by the interaction of a solventand a compound as provided herein or a salt thereof. Suitable solvatesare pharmaceutically or dermatologically acceptable solvates includinghydrates.

Methods of Use and/or Treatment

The compounds and compositions provided herein can be used in methodsfor treating, protecting and/or improving the condition and/or aestheticappearance of skin. For example, the compounds and compositions providedherein can be used in methods for altering the aesthetic appearance ofskin associated with or affected by, or for treating or preventing, finelines and/or wrinkles of skin caused by, for example, cellularsenescence, environmental damage or dermatoheliosis. The disclosure alsorelates to methods for stimulating skin cell renewal, increasing cell ortissue regeneration, promoting fibroblast proliferation and synthesizingelastin, collagen, proteoglycans, and/or new connective tissue, therebyreducing or improving the appearance of wrinkles, restoring elasticity,resiliency, and/or suppleness to the skin. Such methods includeadministering to a subject in need thereof an effective amount of acompound according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II,IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV, ora dermatologically acceptable salt thereof.

The compounds and compositions provided herein can be useful forimproving the aesthetic appearance of skin. Such improvements caninclude, but are not limited to, all outward visibly and tactilelyperceptible manifestations as well as any other macro or micro effectsdue to skin aging and damage. Such manifestations and effects can beinduced or caused by intrinsic factors and/or extrinsic factors, e.g.,chronological aging, environmental damage, climate, sun (UV) exposure,smoking, drugs, alcohol consumption, jetlag, night work, changes incircadian rhythm, pregnancy, menopause, genetic factors, nutritionalfactors and/or deficiencies, dehydration, stress, allergies (e.g., toplants, animals, medications, and other substances), exposure toindustrial and/or household chemicals, indoor heating and cooling,various disorders and diseases such as arteriosclerosis, diabetes, heartdisease, liver disease, and obesity, thinning of the outer layer ofskin, decreases in the number of pigment-containing cells, increases inthe size of pigment-containing cells, changes in the connective tissue,and reduction in the strength and elasticity of the skin.

The aesthetic appearance of skin can be improved, for example, byimproving the appearance of skin associated with or affected by one ormore of wrinkles, dry skin, sensitive skin; wrinkling and sagging; acne;vitiligo (skin condition in which there is a loss of brown color(pigment) from areas of skin); fine lines, wizened skin, thinning of thedermis, the degradation of collagen fibers, flaccid skin, thinned skin,and skin exposed to ultraviolet radiation. In some embodiments, acompound or composition can improve the aesthetic appearance of skin bydecreasing the appearance of fine lines in the skin; creating a moreyouthful appearance of the skin; decreasing bags and/or rings around theeyes; increasing or restoring the elasticity, resiliency, and/orsuppleness of the skin; increasing the apparent thickness, elasticity,flexibility, radiance, glow, and plumpness of the skin; improving thefineness of the skin texture; improving the appearance of wrinkles,lined, dry, flaky, aged, and/or photodamaged skin; treating orpreventing photodamaged skin; reducing the signs of skin aging; reducingthe appearance of hyperpigmentation; treating or preventinghyperpigmentation; treating or preventing pigment deposition in the skin(e.g., that caused by UV exposure); reducing the appearance of skindiscolorations; and whitening, lightening, and/or bleaching the skin.

The compounds and compositions provided herein can also be used inmethods of treating or preventing a skin condition or disorder. Forexample, a compound or composition can improve the aesthetic appearanceof the skin by promoting proliferation and/or mobility of skinkeratinocytes and/or dermis fibroblasts; improving epidermal cell repairactivity; increasing fibroblast proliferation, keratinocyteproliferation, and/or expression of collagen; reducing collagenaseactivity; treating or preventing a wound healing disorder; increasingthe thickness of the epidermis; and inhibiting melanin production.

In one embodiment, the present disclosure provides a method forimproving the condition and aesthetic appearance of skin. The methodcomprising administering to a subject an effective amount of a compoundaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method for alteringthe aesthetic appearance of skin associated with or affected by skinaging. The method comprising administering to a subject an effectiveamount of a compound according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig,Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV.

In one embodiment, the present disclosure provides a method for alteringthe aesthetic appearance of skin associated with or affected byenvironmental damage to the skin. The method comprising administering toa subject an effective amount of a compound according to Formula I, Ia,Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III,IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method for alteringthe aesthetic appearance of skin associated with or affected by one ormore of wrinkles, dry skin, sensitive skin, and dermatological symptomscaused by ineffective homeostatic regulation of healthy skin. The methodcomprising administering to a subject an effective amount of a compoundaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, IIa, IIb,IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method for alteringthe aesthetic appearance of skin associated with or affected by, ortreating or preventing, a skin condition/disorder (e.g., a skincondition/disorder accompanied with a loss of skin elasticity). Themethod comprising administering to a subject an effective amount of acompound according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II,IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method forimproving the barrier function and viability of the skin. The methodcomprising administering to a subject an effective amount of a compoundaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method for alteringthe aesthetic appearance of skin associated with or affected bywrinkling, sagging, and/or a loss of skin elasticity. The methodcomprising administering to a subject an effective amount of a compoundaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method for alteringthe aesthetic appearance of skin associated with or affected by, ortreating or preventing, acne. The method comprising administering to asubject an effective amount of a compound according to Formula I, Ia,Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III,IIIa, IIIb, IIIc, IIId, and/or IV. In some embodiments, the acne can beselected from one or more of simple acne, comedonic acne, papulopustularacne, papulocomedonic acne, nodulocystic acne, acne conglobata, cheloidacne of the nape of the neck, recurrent miliary acne, necrotic acne,neonatal acne, occupational acne, acne rosacea, senile acne, solar acneor medication-related acne.

In one embodiment, the present disclosure provides a method for alteringthe aesthetic appearance of skin associated with or affected bydeteriorations in skin viscoelasticity. The method comprisingadministering to a subject an effective amount of a compound accordingto Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc,IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In another embodiment, the disclosure relates to the use of a compoundaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV foraltering the aesthetic appearance of skin associated with or affected byone or more of wrinkles and/or fine lines, wizened skin, a lack ofelasticity and/or of tonus of the skin, thinning of the dermis,degradation of collagen fibers, flaccid skin, thinned skin, and theinternal degradation of the skin following exposure to ultravioletradiation.

In one embodiment, the present disclosure provides a method fordecreasing the appearance of fine lines and/or wrinkles in the skin. Themethod comprising administering to a subject an effective amount of acompound according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II,IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method for creatinga more youthful appearance of the skin. The method comprisingadministering to a subject an effective amount of a compound accordingto Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc,IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method fordecreasing the appearance of bags and/or rings around the eyes. Themethod comprising administering to a subject an effective amount of acompound according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II,IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method for reducingthe appearance of hyperpigmentation. The method comprising administeringto a subject an effective amount of a compound according to Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method forincreasing or restoring elasticity, resiliency, and/or suppleness of theskin. The method comprising administering to a subject an effectiveamount of a compound according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig,Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV.

In one embodiment, the present disclosure provides a method forimproving or increasing one or more of the thickness, elasticity,flexibility, radiance, glow, and plumpness of the skin. The methodcomprising administering to a subject an effective amount of a compoundaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method forimproving the fineness of skin texture. The method comprisingadministering to a subject an effective amount of a compound accordingto Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, IIa, IIb, IIc, IId,IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method forimproving the appearance of wrinkled, lined, dry, flaky, aged orphotodamaged skin. The method comprising administering to a subject aneffective amount of a compound according to Formula I, Ia, Ib, Ic, Id,Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb,IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method for alteringthe aesthetic appearance of skin associated with or affected by skindiscolorations. The method comprising administering to a subject aneffective amount of a compound according to Formula I, Ia, Ib, Ic, Id,Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb,IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method forwhitening, lightening, and/or bleaching the skin. The method comprisingadministering to a subject an effective amount of a compound accordingto Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc,IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method for alteringthe aesthetic appearance of skin associated with or affected by, ortreating or preventing, hyperpigmentation. The method comprisingadministering to a subject an effective amount of a compound accordingto Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc,IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method for alteringthe aesthetic appearance of skin associated with or affected by, ortreating or preventing, photodamaged skin. The method comprisingadministering to a subject an effective amount of a compound accordingto Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc,IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method for treatingor preventing pigment deposition in the skin caused by UV exposure. Themethod comprising administering to a subject an effective amount of acompound according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II,IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method for treatingor preventing vitiligo (skin condition in which there is a loss of browncolor (pigment) from areas of skin). The method comprising administeringto a subject an effective amount of a compound according to Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiments, the present disclosure provides a method fortreating or preventing a wound healing disorder in a mammal. The methodcomprising administering to a subject an effective amount of a compoundaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV. Forexample, a compound or composition provided herein can be used as amedicament for preventing and/or treating a bedsore in a mammal.

In one embodiment, the present disclosure provides a method forpromoting proliferation and/or mobility of skin keratinocyte and/ordermis fibroblasts (e.g., to increase skin regeneration). The methodcomprising administering to a subject an effective amount of a compoundaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method forimproving the epidermal cell repair activity, for example, in a human.The method comprising administering to a subject an effective amount ofa compound according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii,II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/orIV.

In one embodiment, the present disclosure provides a method forincreasing fibroblast proliferation, keratinocyte proliferation, and/orexpression of collagen. The method comprising administering to a subjectan effective amount of a compound according to Formula I, Ia, Ib, Ic,Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf III, IIIa,IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method for reducingcollagenase activity. The method comprising administering to a subjectan effective amount of a compound according to Formula I, Ia, Ib, Ic,Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method forincreasing or improving the thickness of the epidermis. The methodcomprising administering to a subject an effective amount of a compoundaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, the present disclosure provides a method forinhibiting melanin production. The method comprising administering to asubject an effective amount of a compound according to Formula I, Ia,Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III,IIIa, IIIb, IIIc, IIId, and/or IV.

The various effects on the skin (e.g., skin conditions/disorders)described above can be caused by or be associated with various internaland external influences.

In some embodiments, the skin condition/disorder is caused by orassociated with aging.

In some embodiments, the skin condition/disorder is caused by orassociated with environmental factors.

In some embodiments, the skin condition/disorder is caused by orassociated with genetic factors.

In some embodiments, the skin condition/disorder is caused by orassociated with nutritional factors and/or deficiencies.

In some embodiments, the skin condition/disorder is caused by orassociated with blood vessel diseases such as arteriosclerosis.

In some embodiments, the skin condition/disorder is caused by orassociated with dehydration.

In some embodiments, the skin condition/disorder is caused by orassociated with diabetes.

In some embodiments, the skin condition/disorder is caused by orassociated with heart disease.

In some embodiments, the skin condition/disorder is caused by orassociated with liver disease.

In some embodiments, the skin condition/disorder is caused by orassociated with obesity.

In some embodiments, the skin condition/disorder is caused by orassociated with stress.

In some embodiments, the skin condition/disorder is caused by orassociated with allergies to plants and other substances.

In some embodiments, the skin condition/disorder is caused by orassociated with climate.

In some embodiments, the skin condition/disorder is caused by clothing.

In some embodiments, the skin condition/disorder is caused by exposureto industrial and household chemicals.

In some embodiments, the skin condition/disorder is caused or associatedwith by indoor heating/cooling.

In some embodiments, the skin condition/disorder is caused by orassociated with sunlight (UV exposure).

In some embodiments, the skin condition/disorder is caused by a reactionto a medication (e.g., an adverse reaction).

In some embodiments, the skin condition/disorder is related to thinningof the outer skin layer (epidermis).

In some embodiments, the skin condition/disorder is related to adecrease in the number of pigment-containing cells (melanocytes).

In some embodiments, the skin condition/disorder is related to anincrease in the size of pigment-containing cells (melanocytes).

In some embodiments, the skin condition/disorder is related to enlargedpigmented spots (called age spots, liver spots, or lentigos).

In some embodiments, the skin condition/disorder is related to a changein the connective tissue.

In some embodiments, the skin condition/disorder is related to areduction of the skin's strength and elasticity (elastosis).

In some embodiments, the skin condition/disorder is related to the bloodvessels of the dermis becoming more fragile.

In some embodiments, the skin condition/disorder is related to areduction in oil production (e.g., a reduction in the oil production ofthe sebaceous glands).

In some embodiments, the skin condition/disorder is related to athinning of the subcutaneous fat layer.

In some embodiments, the skin condition/disorder is related to areduction in sweat production by the sweat glands.

In some embodiments, the skin condition/disorder is related to a growthsuch as skin tags and/or warts.

The term “subject” as used herein, means a human or a non-human mammal,e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, anon-human primate, or a bird, e.g., a chicken, as well as any othervertebrate or invertebrate. In some embodiments, a subject is a human.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes humans, cattle, horses, monkeys, dogs, cats,mouse, rat, a cow, sheep, pig, goat, and non-human primate but alsoincludes many other species.

The phrase an “effective amount” is used to mean a “therapeuticallyeffective amount” or “cosmetically effective amount” depending on theintended use of the compound or composition to which it refers. Aneffective amount as used herein means an amount of a compound orcomposition sufficient for achieving a desirable result in response toone or more skin conditions/disorders, but low enough to avoid seriousside effects. The effective amount of the compound or composition willvary with the particular condition being treated, the age and physicalcondition of the end user, the severity of the condition beingtreated/prevented, the duration of the treatment, the nature of othertreatments, the specific compound or product/composition employed, theparticular carrier utilized, and like factors. “Effective amount” isalso intended to include one or more of the compounds of Formula I, Ia,Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III,IIIa, IIIb, IIIc, IIId, and/or IV, or a dermatologically acceptable saltthereof, in combination with one or more other agents that have anintended cosmetic or dermopharmaceutical effect. The combination ofcompounds can be a synergistic combination. Synergy, as described, forexample, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22,27-55, occurs when the effect of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at sub-optimal concentrations of thecompounds.

“Treat,” “treatment,” or “treating,” as used herein means reversing,alleviating (e.g., reducing or eliminating) one or more symptoms of,inhibiting the progress of, and/or delaying, either partially orcompletely, a disease or disorder of the skin including, for example,the skin conditions/disorders described herein.

The term “skin condition/disorder” includes, but is not limited to, oneor more of aging skin, skin exposed to excessive sunlight (e.g.photoaged or photo damaged skin), age spots, unwanted wrinkles, finelines, crevices, bumps, large pores (e.g. associated with adnexalstructures such as sweat gland ducts, sebaceous glands, or hairfollicles), unevenness or roughness of the skin, loss of skin elasticity(e.g., loss in activation of functional skin elastin), sagging(including puffiness in the eye area and j owls), loss of skin firmness,loss of skin tightness, loss of skin recoil from deformation,discoloration (including (black) under eye circles), blotching,sallowness, hyperpigmentation such as age spots and freckles, blemishes,stressed skin, rough skin, dry skin, cellulitis, irritated skin, scars,saggy lips, acne, keratoses, abnormal differentiation,hyperkeratinization, elastosis, collagen breakdown, and otherhistological changes in the stratum corneum, dermis, epidermis, the skinvascular system (e.g., telangiectasia or spider vessels), and underlyingtissues, especially those proximate to the skin.

The term “wound” as used herein refers broadly to injuries to the skinand subcutaneous tissue initiated in any one of a variety of ways (e.g.,pressure sores from extended bed rest, wounds induced by trauma, woundsreceived during or following a surgical procedure and the like) and withvarying characteristics. Exemplary examples include, but are not limitedto, bruises, scrapes, burn wounds, sunburn wounds, incisional wounds,excisional wounds, surgical wounds, necrotizing fascitis, ulcers, venousstasis ulcers, diabetic ulcers, decubitus ulcers, aphthous ulcers,pressure ulcers, scars, alopecia areata, dermatitis, allergic contactdermatitis, atopic dermatitis, berloque dermatitis, diaper dermatitis,dyshidrotic dermatitis, psoriasis, eczema, erythema, warts, anal warts,angioma, cherry angioma, athlete's foot, atypical moles, basal cellcarcinoma, Bateman's purpura, bullous pemphigoid, candida,chondrodermatitis helicis, Clark's nevus, cold sores, condylomata,cysts, Darier's disease, dermatofibroma, Discoid Lupus Erythematosus,nummular eczema, atopic eczema, dyshidrotic eczema, hand eczema,Multiforme Erythema Nodosum, Fordyce's Condition, FolliculitisKeloidalis Nuchae, Folliculitis, Granuloma Annulare, Grover's Disease,heat rash, herpes simplex, herpes zoster (shingles), HidradenitisSuppurativa, Hives, Hyperhidrosis, Ichthyosis, Impetigo, KeratosisPilaris, Keloids, Keratoacanthoma, Lichen Planus, Lichen Planus LikeKeratosis, Lichen Simplex Chronicus, Lichen Sclerosus, LymphomatoidPapulosis, Lupus of the Skin, Lyme Disease, Lichen Striatus, MyxoidCysts, Mycosis Fungoides, Molluscum Contagiosum, Moles, Nail Fungus,Necrobiosis Lipoidica Diabeticorum, Nummular Dermatitis, Onychoschizia,Onychomycosis, Pityriasis Lichenoides, Pityriasis Rosea, PityriasisRubra Pilaris, Plantar Warts, Poison Ivy, Poison Oak, Pompholyx,Pseudofolliculitis Barbae, Pruritus Ani and Pityriasis Alba.

Evaluation of Biological Activity

The biological activity of the compounds and compositions describedherein can be tested using any suitable in vivo or in vitro test. Forexample, the compounds and compositions can be evaluated using in vitroor in vivo assays, subjective evaluations of patients, and mechanicalassays used to measure and evaluate physical parameters of the skin.Various factors can be used to determine the effectiveness of a compoundor composition provided herein. Such factors include changes to thedepth of wrinkles, changes in the frequency of wrinkles, changes in thefrequency of acne, skin elasticity and firmness, and subject complianceand satisfaction.

Mechanical properties of the skin change not only with aging but alsoupon exposure to various environmental factors like UV irradiation andair pollution. This exposure can lead to decreases in the synthesis ofcollagen as well as damage due to processes like glycation or oxidativestress. Fibroblasts are major cell types present in the dermis, whichare capable of producing collagen fibers—the main component of theextracellular matrix (ECM) of the dermal connective tissue. Fibroblastsare also thought to be connected with the collagen network and providedermal support for the epidermis and give rise to elastic properties ofa tissue.

A change in elastic properties of cells can be determined using atomicforce microscopy to calculate the relative Young's modulus (a parameterdescribing the elastic properties of cells). This method is describedin, for example, International Journal of Peptide Research andTherapeutics (2014), 20(1), 77-85. Another exemplary method usesinfrared thermography in combination with a mechanical deformationsystem to measure skin elasticity and firmness (see, e.g., U.S. PatentApplication No. 2013/0079643). Skin elasticity can also be measuredusing a Cutometer® (Courage+Khazaka electronic GmbH, Germany) byslightly pressing a testing probe on the skin resulting in a temporaryvacuum. The skin is lifted, stretched and then released. Thesedeflections can be optically recorded and evaluated as demonstrated inU.S. Patent Application No. 2005/0054578 (see., e.g., Example 13).Methods for determining skin moisturizing effects are shown in U.S.Patent Application No. 2013/0171274 (see. e.g., Example 5).

The effects of photo-aging on the skin can be determined by evaluatingthe ultraviolet light (UV)-induced photodimerization of thymine, theexpression of the proinflammatory cytokine interleukin (IL)1-α, thefree-radical scavenging properties of the skin by quantification of thebiomarker of oxidative stress malondialdehyde (MDA), as well as theantiglycation activity (glycation reduces the ability of collagen fiberto regenerate, leading to skin wrinkling). Examples of related tests areshown in, for example, Clinical, cosmetic and investigationaldermatology (2013), 7, 1-9. The expression of proinflammatorymatrixmetalloproteinases (MMPs), production of reactive oxygen species(ROS) and NF-κB signaling (all indicators of UVB-induced photoaging) canbe determined by methods described in, for example, PLoS One (2013),8(9), e73877. Other non-limiting examples of such assays can be found inAmerican Journal of Chinese Medicine (2010), Journal of DermatologicalScience, Supplement (2006), 2(1), S65-S74, WO 2008/156345, and U.S. Pat.No. 8,741,357.

Wrinkle prevention can be evaluated using hairless mice exposed tochronic solar-simulating ultraviolet (UV) irradiation as demonstrated inEuropean journal of pharmacology (2001), 411(1-2), 169-174,International journal of dermatology (2006), 45(4), 460-8, BMB reports(2013), 46(9), 465-70, U.S. Pat. No. 8,088,369 (e.g, Examples 1 and 2),and WO 2008/001921.

Mechanical and optical methods can also be used to measure wrinkles.Non-limiting examples of such instruments and methods include PRIMOShigh resolution (GFMesstechnik, Germany) which can quantify periorbitalwrinkles (crows feet), perioral wrinkles (around mouth and lips),nasiolabial wrinkles (cheek, forehead wrinkles, and/or frowningwrinkles), and glabella wrinkles (between the eye brows) by optical 3Dmeasurement of the skin; and Antera 3D® (Miravex Limited, Ireland) whichallows for a view of skin in 2 and 3 dimensions as well asmulti-spectral analysis of epidermis and dermis. The scan can provideinformation on how rough the skin is, how deep the wrinkles are, and thedegree of sun damage and redness. FOITS (Fast Optical in vivo Topometryof Human Skin) (Schrader Institute, Germany) is a non-contact method of3D wrinkle analysis. This 3D wrinkle method methodology allows forquantification of the surface topography of the skin and excludes skincolor tone and surface reflection artifacts. The in-vivo-3D Breuckmannscanner (AICON, Michigan, USA) uses an imaging metrology principle basedon structured light projection, and a combination of GrayCode- andPhaseshift technology. The Visioscan® (Courage+Khazaka electronic GmbH,Germany) uses a UVA-light video camera with high resolution to study theskin surface directly. The images show the structure of the skin and thelevel of dryness of the skin. The software analyses the grey leveldistribution and allows for the calculation of four clinical parametersto quantitatively and qualitatively describe the skin surface as anindex: skin smoothness, skin roughness, scaliness, and wrinkles.

Other non-limiting examples of devices include the Corneometer®, whichcan be used to determine the hydration level of the skin surface(Stratum corneum); the Mexameter®, which can be used to measure the twocomponents mainly responsible for the color of the skin: melanin andhemoglobin (erythema) by reflectance; the Tewameter®, which evaluatesthe water barrier function of the skin; the CutiScan®, which measuresthe mechanical properties of the skin (viscoelasticity & anisotropy);and the Visiopor®, which uses a specific UV-light to visualizefluorescing acne lesions.

Administration and Cosmetic and Dermopharmaceutical Compositions

Also provided herein are cosmetic or dermopharmaceutical compositionscomprising: (a) an effective amount of a compound provided herein, orits corresponding enantiomer, diastereoisomer or tautomer, ordermatologically acceptable salt thereof; and (b) a dermatologicallyacceptable carrier.

The compounds provided herein may also be useful in combination(administered together) with other known ingredients.

Based on the intended use, the compositions can be care, treatment,cleansing, and/or protective products for facial or body skin;anti-wrinkle or anti-aging compositions; skin firming compositions; skinlightening compositions; compositions for irritated skin; sunscreencompositions, artificial tanning (self-tanning) compositions orafter-sun care compositions; scalp care compositions; shavingpreparation compositions; depilatory compositions; or make-up productsfor the skin of the face or body.

The cosmetic and dermopharmaceutical compositions of the presentdisclosure can be prepared and used in the form of an aerosol spray,cream, emulsion, solid, liquid, dispersion, foam, oil, gel, lotion,mousse, ointment, powder, patch, pomade, solution, pump spray, stick,towelette, soap, or other forms commonly employed in the art of topicaladministration and/or cosmetic and skin care formulation. Thecompositions can be in an emulsion form. In addition, compounds providedherein used in the compositions provided herein can be used in colorcosmetic compositions such as foundation makeups, blushes, eyeshadows,mascaras, concealers, eyeliners, lip colors, nail colors, and so on.Other cosmetic compositions can include perfumes, lipsticks, fingernailand toe nail polish, eye and facial makeup, towelettes, deodorants, handsanitizer, baby products, bath oils, bubble baths, and butters. Thecosmetic and dermopharmaceutical compositions of the present disclosurecan be formulations for subcutaneous injection.

If desired, formulations of the disclosure can be incorporated into agel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).

The compounds provided herein are intended for cosmetic and/ordermopharmaceutical use and can be administered as crystalline oramorphous products. Cosmetic or dermopharmaceutical compositions asprovided herein can include solid, semi-solid, liquid, solutions,colloidal, liposomes, emulsions, suspensions, complexes, coacervates andaerosols. Dosage forms, such as, e.g., powders, liquids, suspensions,suppositories, aerosols, controlled release or the like, are providedherein. The dosage forms can be obtained, for example, as solid plugs,powders, lipid nanoparticles, or films by methods such as precipitation,crystallization, milling, grinding, supercritical fluid processing,coacervation, complex coacervation, encapsulation, emulsification,complexation, freeze drying, spray drying, or evaporative drying.Microwave or radio frequency drying may also be used.

Liquid cosmetic or dermopharmaceutical compositions can, for example, beprepared by dissolving, dispersing, etc. a compound as provided hereinand optional cosmeceutical/cosmetic/dermatological adjuvants in acarrier (e.g., water, saline, aqueous dextrose, glycerol, glycols,ethanol or the like) to form a solution, colloid, liposome, emulsion,complexes (including inclusion complexes), coacervate, or suspension. Ifdesired, the cosmetic and/or dermatological composition can also containauxiliary substances such as wetting agents, emulsifying agents,co-solvents, solubilizing agents, pH buffering agents, and the like(e.g., sodium acetate, sodium citrate, cyclodextrins and derivatives,sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate,hydroxyethylpiperazine and the like).

In some embodiments, the cosmetic or dermopharmaceutical compositioncomprises a combination of a compound of Formula I, Ia, Ib, Ic, Id, Ie,If, Ig, Ih, Ii, II, IIa, lib, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc,IIId, and/or IV and one or more additional ingredients, carriers,excipients, or diluents including, but not limited to, absorbents,anti-irritants, antibacterials, anti-acne agents, antioxidants, coloringagents/pigments, emollients (moisturizers), emulsifiers,film-forming/holding agents, fragrances, leave-on exfoliants,prescription drugs, preservatives, scrub agents, silicones,skin-identical/repairing agents, slip agents, sunscreen actives,surfactants/detergent cleansing agents, penetration enhancers, andthickeners.

Lists of ingredients, which are well known in the art, are disclosed,for example, in “Cosmetics: Science and Technology,” edited by M. S.Balsam and E. Sagarin, 2nd Edition, 1972, Wiley Pub. Co.; “The Chemistryand Manufacture of Cosmetics” by M. G. DeNavasse; and “Harry'sCosmeticology,” J. B. Wilkinson et al., 7th Edition, 1982, Chem. Pub.Co.; the disclosures of each of the above being incorporated herein byreference in their entirety.

In some embodiments, diluents, carriers, and excipients may include, butare not limited to, polyethylene glycols (such as PEG200, PEG300,PEG400, PEG540, PEG600, PEG1450 or mixtures thereof) and coconut oils(such as propylene glycol dicaprate, coco-caprylate/caprate, propyleneglycol dicaprylate/dicaprate, caprylic/capric triglyceride,caprylic/capric/lauric triglyceride, caprylic/capric/linoleictriglyceride, tricaprin, tricaprylin, glyceryl trioleate, neopentylglycol dicaprylate/dicaprate, caprylic/capric/palmitic/stearictriglceride, or mixtures thereof).

Absorbents are substances which are added to cosmetic/dermatologicalproducts to take up water and oil-soluble dissolved or finely dispersedsubstances. Cosmetic/dermatological chemical absorbents can also be usedas cosmetic/dermatological thickeners in a wide variety of formulationsincluding facial creams, lipsticks, shampoos and calamine lotions.

In some embodiments, absorbents may include, but are not limited to,alcohol (ethyl alcohol, methanol, isopropyl alcohol, SD alcohol[especially denatured alcohol] and benzyl alcohol), alumina (aluminumoxide), aluminum chlorohydrate, aluminum hydroxide, aluminum magnesiumsilicate, aluminum silicate, aluminum starch octenylsuccinate, aluminumsulfate, ammonium chloride, bentonite, bismuth oxychloride, boronnitride, calcium carbonate, carnauba wax, charcoal, China clay, clay,Copernicia cerifera wax, cornstarch, fuller's earth, hydrolyzed cornstarch, iron powder, kaolin, lithium magnesium sodium silicate,magnesium, magnesium carbonate, magnesium hydroxide, montmorillonite,nylon-12, rice starch, silica, silicate, silk powder, silt, sodiumcarbonate, sodium polyacrylates, and zeolite.

Anti-Irritants are substances which are added to cosmetic/dermatologicalproducts to reduce certain signs of inflammation, such as swelling,tenderness, pain, itching, or redness. Many ingredients perform thefunction of anti-irritants or anti-inflammatories. Many antioxidantsalso function as anti-irritants because one of the skin's responses tofree-radical damage is irritation and inflammation. These ingredientshelp the skin deal with sun exposure, pollution, skin-care routines(topical disinfectants, sunscreens, and exfoliants can be irritating toskin), and seasonal environmental extremes [Exogenous Dermatology(2004), 3(4), 154-160; and Toxicology Letters (2003), 146(1), 65-73].

In some embodiments, anti-irritants may include, but are not limited to,Acacia senegal, acetylsalicylic acid, Achillea millefolium, adenosine,adenosine triphosphate, Aesculus hippocastanum, allantoin, Aloebarbadensis, aloe barbadensis leaf juice extract, aloe extract, aloejuice, aloe vera, alpha bisabolol, Althaea rosea, Althea officinalis,aminobutyric acid, andiroba oil, Anthemis nobilis flower extract,Arachis hypogaea extract, Arctium lappa, adenosine triphosphate, Avenasativa, azulene, barberry, β-hydroxy acids (BHA) (such as salicylicacid, β-hydroxybutyric acid, tropic acid and trethocanic acid),β-glucan, β-sitosterol, bisabolol, black tea, Boerhavia diffusa rootextract, borage seed extract, borage seed oil, Borago officinalisextract, Borago officinalis seed oil, burdock root, butcher's broomextract, calcium gluconate, Calendula extract, Calluna vulgaris flowerextract, canola oil, Centaurea cyanus, chitosan, chrysanthemum extract,coenzyme Q₁₀ (ubiquinone), colloidal oatmeal, comfrey extract,coneflower, cornflower, Cornus extract, cranberry seed extract,curcumin, decarboxy carnosine HCL, dipotassium glycyrrhizate,dipotassium glycyrrhizinate, dogwood, epidermal growth factor (EGF),epigallocatechin gallate, Epilobium angustifolium extract,ergothioneine, evening primrose oil, Evodia rutaecarpa extract, feverfewextract, Filipendula rubra, fireweed extract, Fu ling, genistein,Gentiana lutea (Gentian) root extract, ginger extract, ginger oil,glabridin, glycyrrhetic acid, Glycyrrhiza glabra, Glycyrrhiza uralensisroot extract, green tea, gromwell, honey, honey extract, honeysuckleflower extract, horse chestnut extract, hydrocortisone, Ilexparaguariensis, Ju hua, jujube fruit extract, juniper berry, Juniperuscommunis, kava-kava extract, kawa extract, Kigelia africana extract,L-ascorbic acid, Laminaria ochroleuca extract, Lamium album flowerextract, lappa extract, Leontopodium alpinum extract, licorice extract,licorice root, linoleic acid, Lithospermum erythrorhizon, Loniceracaprifolium flower extract, Lonicera japonica, Lonicera japonica flowerextract, lotus seed extract, Luffa cylindrica seed oil or extract,mallow, Malva sylvestris extract, marigold, marshmallow, mate extract,Matricaria flower extract, meadowsweet extract, Morinda citrifolia,nettle extract, niacinamide, noni juice, oat β-glucan, oat bran extract,oatmeal, Oenothera biennis oil, oleanolic acid, opium poppy seed, P.elisabethae, pansy extract, Perilla ocymoides, petrolatum, Phyllanthusemblica fruit extract, Picea excelsa extract, Poria cocos extract,Portulaca oleracea extract, propolis, Prunella vulgaris,Pseudopterogorgia elisabethae, red clover, resveratrol, Ruscusaculeatus, salicin, salicylic acid, Salix alba extract, Salix nigra(willow) bark extract, Sapindus mukurossi peel extract, saponin, sawpalmetto extract, Scutellaria baicalensis extract, sea whip extract,self-heal, Serenoa serrulata extract, silver tip white tea leaf extract,skullcap extract, slippery elm bark, soapberry extract, sodium ascorbylphosphate, Sonojell, soy extract, soy isoflavones, soy oil, soy protein,Spiraea ulmaria, stearyl glycyrrhetinate, Symphytum officinale extract,tamanu oil, Tanacetum parthenium, Tazorac, Terminalia sericea,Terminalia sericea extract, tetrahydrobisdemethoxycurcumin,tetrahydrodemethoxycurcumin, tetrahydrodemethoxydiferuloylmethane,tetrahydrodiferuloylmethane, tetrahydro-methoxycurcumin, Trifoliumpretense, turmeric, Ulmus fulva bark extract, Ulva lactuca extract,Urtica dioica, Vaccinium macrocarpon fruit extract, Vanilla planifoliafruit extract, Viola tricolor extract, white nettle, white willow, wildginger, willow bark, willow herb, witch hazel, Xi xin, yarrow extract,yerba mate extract, Yucca extract, zinc, zinc oxide, Zingiber officinaleroscoe, Zingiber zerumbet, Zingiberaceae, and Zizyphus jujuba fruitextract.

Antibacterial ingredients are substances which are added tocosmetic/dermatological products to destroy or inhibit the growth ofbacteria; in the case of skin-care products, particularly the bacteriathat cause blemishes.

Anti-acne ingredients are substances which are added tocosmetic/dermatological products to help to reduce and control acne, andacne related problems such as sebum production. Some agents work byincreasing skin cell turnover promoting the extrusion of the pluggedmaterial in the follicle.

In some embodiments, antibacterial and/or anti-acne agents may include,but are not limited to, Alchemilla vulgaris, Aleurites moluccana seedoil, aluminum sulfate, amygdalic acid, anise, Anthemis nobilis flowerextract, Arctostaphylos uva ursi leaf, Azadirachta indica, barberry,benzalkonium chloride, benzoin extract, benzoyl peroxide, Berberisaristata, β-hydroxy acids (BHA) (such as salicylic acid,β-hydroxybutyric acid, tropic acid and trethocanic acid), borate, boricacid, calendula extract, Centella asiatica, chamomile, Chamomillarecutita flower extract, chaparral extract, chaulmoogra oil, chitosan,chlorhexidine, chloroxylenol, Cinnamomum, cinnamon, colloidal silver,Commiphora myrrha extract, Cymbopogon citrates, Epilobium angustifoliumextract, eucalyptus extract, eucalyptus oil, farnesol, farnesyl acetate,Gentiana lutea (Gentian) root extract, geranium oil, Geranium pretense,glucose oxidase, goldenseal, gotu kola, hoelen, hops, Humulus lupulusextract, Hydnocarpus anthelmintica, Hydrastis canadenis, hydrocotylextract, hyssop, Illicium vernum, jujube fruit extract, lactoperoxidase,lady's mantle extract, Larrea divaricata extract, Larrea tridentata,lemon, lemongrass extract, Lentinus edodes extract, Leptospermumscoparium oil, magnesium, magnesium gluconate, magnesium hydroxide,manuka oil, marigold, Matricaria oil, Melaleuca alternifolia, Meliaazadirachta, Mentha piperita, menthol, menthone, Mitracarpe scaberextract, myrtle extract, Myrtus communis extract, Nardostachysjatamansi, neem extract or oil, oak root extract, oregano, Origanumvulgare flower extract, P. elisabethae, palmarosa oil, Pelargoniumgraveolens oil, peppermint, pine oil, pinecone extract, Pinus sylvestrisextract, propolis, Pseudopterogorgia elisabethae, pyridoxinehydrochloride (HCL), quercus, Quercus infectoria extract, quillajaextract, Ranunculus ficaria extract, raspberry seed extract, raspberryseed oil, red raspberry extract, resorcinol, Rubus idaeus, Saponariaofficinalis extract, silver, soapwort, sodium ascorbyl phosphate, sodiumsilicate, spikenard, star anise, sulfur, Taraktogenos kurzii, tea treeoil, Terminalia sericea extract, tretinoin, triclosan, Uva ursi extract,vetiver oil or extract, white oak bark extract, willow herb, zincphenolsulfonate, and Zizyphus jujuba fruit extract.

Antioxidants ingredients are substances which are added tocosmetic/dermatological products to reduce free-radical damage andenvironmental stress on skin [Clinics in Dermatology (2008), 26(6),614-626; Skin Therapy Letter (2008), 13(7), 5-9; and Journal of Drugs inDermatology (2008), 7(2), S7-S12]. Antioxidants are useful in two ways:They prevent degradation of natural ingredients (proteins, sugars,lipids) in the cosmetic product. Antioxidants also protect the skincells from being damaged and slow down the aging process. Antioxidantshave been shown to boost the skin's radiance, minimize age spots, sunspots, and fine lines.

In some embodiments, antioxidants may include, but are not limited to,Acai, acetyl carnitine HCL, agar, Agrimonia eupatoria leaf extract,Ahnfeltia concinna extract, Ahnfeltia extract, alanine, Alariaesculenta, alfalfa extract, algae, algae extract, algin, α-lipoic acid,α-tocopherol, Anacystis nidulans extract, Angelica archangelica rootoil, Angelica polymorpha sinensis root extract, anise, Anthemis nobilisflower extract, anthocyanin, Arctium lappa, Arctostaphylos uva ursileaf, argan oil, Argania spinosa, arginine, artemia extract, Ascophyllumnodosum, ascorbic acid, ascorbyl glucosamine, ascorbyl glucoside,ascorbyl methylsilanol pectinate, ascorbyl palmitate, asparagine,Asparagopsis armata extract, aspartic acid, astaxanthin, astaxanthinextract, Astragalus membranaceus, Astragalus sinicus, avocado oil,azulene, banana extract, bay leaf oil, beet root extract, Bertholletiaexcelsa extract, 3-hydroxy acids (BHA) (such as salicylic acid,β-hydroxybutyric acid, tropic acid and trethocanic acid), β-vulgarisroot extract, β-carotene, β-glucan, Betula alba, Butylatedhydroxytoluene, bioflavonoids, birch bark extract, birch leaf extract,black elderberry, black locust extract, black raspberry, black tea,blackberry, bladderwrack extract, Boerhavia diffusa root extract, borageseed oil, Borago officinalis extract, Borago officinalis seed oil,boysenberry, Brassica campestris, Brazil nut extract, Buddleja davidiiextract, burdock root, caffeic acid, caffeine, calcium ascorbate,calendula extract, Calendula officinalis flower extract, Camelliajaponica, Camellia oleifera, Camellia sinensis, carnitine, carnosicacid, carnosine, carnosol acid, catalase, Caulerpa taxifolia extract,chamomile, Chamomilla recutita flower extract, chaparral extract,chlorella, cholecalciferol, Chondrus crispus, Cichorium intybus,Cinnamomum, cinnamon, Citrus unshiu, Citrus unshiu peel extract, cocoaextract, Codium tomentosum extract, coenzyme Q₁₀ , Coffea arabica(coffee) seed oil, Coffea arabica extract, collagen amino acids, coppergluconate, copper peptides, Corallina officinalis extract, Cornusextract, coumarin, cranberry seed extract, cranberry seed oil, cucumberextract, Cucumis melo (melon) fruit extract, Cucumis sativus extract,Cucurbita pepo seed extract, Cucurbitea peponis, curcumin, Cymbopogonmartini, D-α-tocopherol, Daucus carota, diethylhexylsyringylidenemalonate, disodium rutinyl disulfate, dogwood, Angelicapolymorpha sinensis, dulse, durian, Durvillaea antarctica extract,Elaeis guineensis, elderberry, ellagic acid, Enteromorpha compressaextract, epigallocatechin gallate, ergocalciferol, ergothioneine,Eriobotrya japonica, escin, ethyl vanillin, Euterpe oleraca, faex, Fagussylvatica extract, farnesol, farnesyl acetate, fennel seed extract,Ferula foetida, ferulic acid, Filipendula glaberrima, flavonoid, flax,flaxseed oil, Foeniculum vulgare extract, folic acid, Fu ling, Fucusvesiculosus extract, galactoarabinan, γ-linolenic acid (GLA), Ganodermalucidum extract, Gardenia florida extract, Gellidiela acerosa extract,genistein, geranium extract, Geranium pretense, Ginkgo biloba leafextract, glutathione, Glycine soja oil, grape seed extract, grape seedoil, green tea, gromwell, Haematococcus pluvialis extract, Hamamelisvirginiana, hamamelitannin, Haslea ostrearia extract, hawthorn extract,hesperidin, hesperidin methyl chalcone, hexylresorcinol, hibiscus,Himanthalia elongate extract, Hippophae rhamnoides, histidine, honey,honey extract, hops, Hordeum vulgare extract, horsetail extract, Huangqi, Humulus lupulus extract, hydrogenated olive oil, hydrogenated palmglycerides, hydrolyzed silk, hydroquinone, Hypericum extract, idebenone,Ilex paraguariensis, Illicium vernum, Irish moss extract, Isoflavone,isoleucine, jojoba butter, kelp extract, Kigelia africana extract, kiwifruit extract, kojic acid, kojic dipalmitate, kudzu root, L-ascorbicacid, L-carnitine, L-cysteine, lady's thistle extract, Laminariadigitata, Laminaria longicruris, Laminaria saccharine, Lamium albumflower extract, lappa extract, Larrea divaricata extract, Larreatridentate, Laurus nobilis, lemon juice, Leontopodium alpinum extract,linden flower extract, linoleic acid, Lithospermum erythrorhizon, loquatextract, lotus seed extract, lupine, lupine oil, Lupinus albus extract,lutein, Lycium barbarum fruit extract, lycopene, lysine, magnesiumascorbyl palmitate, magnesium ascorbyl phosphate, Malva sylvestrisextract, manganese gluconate, Mangifera indica root, marigold,marionberry, Mastocarpus stellatus, mate extract, matricaria flowerextract, matricaria oil, Me di cago sativa, methionine, methyl sufonylsulfate, Microcystis aeruginosa, milk vetch root, Morinda citrifolia,N-acetyl-L tyrosine, Nasturtium officinale extract, natto gum, nonijuice, nordihydroguaiaretic acid, Nymphaea tetragona, oat β-glucan, oatbran extract, Olea europaea fruit oil, Olea europaea oilunsaponifiables, oleanolic acid, olive oil/olive fruit oil, oryzanol,oxidoreductase, Padina pavonica extract, Paeonia suffruticosa extract,palm oil, Palmaria palmata extract, Panax ginseng root extract, pansyextract, Passiflora edulis seed oil, peony root extract, Perillaocymoides, Persea gratissima oil, Persicaria hydropiper, phenylalanine,phenylethyl resorcinol, phloretin, Phyllanthus emblica fruit extract,phytic acid, pinecone extract, Pinus sylvestris extract, Pisum sativum,plum extract, Polygonum cuspidatum root extract, polysaccharide,pomegranate extract, Poria cocos extract, potassium ascorby tocopherylphosphate, proline, Prunella vulgaris, Prunus Americana, Prunusdomestica seed extract, Pueraria lobata, pullulan, pumpkin, pumpkin seedextract, Punica granatum extract, Pycnogenol, pyridoxine hydrochloride(HCL), quercetin, rapeseed oil, raspberry seed extract, raspberry seedoil, red algae, red clover, red raspberry extract, resveratrol, retinol,retinyl palmitate, Robinia pseudacacia extract, Rosa canina, Rosacentifolia, Rosa centifolia flower, Rosa eglanteria, Rosa mosqueta, Rosaroxburghii extract, Rosa rubiginosa, rose hip, rose hip oil, rosemaryextract, rosemary oil, Rosmarinus officinalis extract, Rubus idaeus,Rubus occidentalis, Rubus ursinus, Rubus ursinus x idaeus, Rubusvilloscus, rutin, Saccharomyces copper ferment, Saccharomyces ironferment, Saccharomyces lysate, Saccharomyces magnesium ferment,Saccharomyces manganese ferment, Saccharomyces potassium ferment,saccharomyces selenium ferment, Saccharomyces silicon ferment, safflowerseed oil, Sambucus Canadensis, Sambucus cerulean, Sambucus nigra,Sapindus mukurossi peel extract, saponin, Sargassum filipendula extract,Scutellaria baicalensis extract, sea buckthorn, Seamollient, seaweed,selenium, self-heal, sericin, serine, Shao-yao, silk, silk protein,silver tip white tea leaf extract, skullcap extract, soapberry extract,sodium ascorbate, sodium ascorbyl phosphate, sodium citrate, sodiummetabisulfite, Solanum lycopersicum extract, soy extract, soyisoflavones, soy oil, soy protein, spirulina, squalane, squalene, St.John's wort, star anise, superoxide dismutase, Tamarindus indica seedextract, tannic acid, Terminalia catappa, tetradibutyl pentaerithritylhydroxyhydrocinnamate, tetrahexyldecyl ascorbate,tetrahydrobisdemethoxycurcumin, tetrahydrobisdemethoxydiferuloylmethane,tetrahydrodemethoxycurcumin, tetrahydro-demethoxydiferuloylmethane,tetrahydrodiferuloylmethane, tetrahydromethoxycurcumin, thioctic acid,thiodipropionic acid, thiotaurine, threonine, thyme extract, thyme oil,Thymus serpillum extract, Thymus vulgaris, Thymus vulgaris oil, Tiliacordata, tocopherol, tocopherol acetate, tocopheryl acetate, tocopheryllineolate, tocotrienols, tomato extract, Trifolium pretense, tryptophan,turmeric, Ulva lactuca extract, Undaria pinnatifida, Vacciniummacrocarpon fruit extract, valine, Vanilla planifolia fruit extract,Viola tricolor extract, vitamin A, vitamin C, vitamin D, vitamin E,vitamin F, Vitis vinifera, walnut extract, watercress extract, whey,white tea leaf extract, witch hazel, yeast, yerba mate extract, yuccaextract, zinc, and zinc oxide.

Coloring Agents/Pigments are any dye, pigment, or substance that impartscolor when added or applied to a food, drug, cosmetic/dermatological, orto the human body and which are deemed to be safe and FDA-approved foruse in foods, drugs, and cosmetics. Most organic colorants are syntheticand are available as either water soluble, oil soluble or insoluble(=Lakes) agents in all kinds of shades. Inorganic colorants are composedof insoluble metallic compounds which are either derived from naturalsources (e.g. china clay, carbon deposits) or synthesized.

In some embodiments, coloring agents/pigments may include, but are notlimited to, aluminum powder, barium sulfate, beet root extract,0-vulgaris root extract, blue 1, blue 1 lake, bronze powder, caramel,carmine, chromium hydroxide green, chromium oxide green, D&C (drugs &cosmetics) colors, Ext. D&C (external drugs and cosmetics) colors, FD&C(food, drug and cosmetic) colors, ferric ammonium ferrocyanide, ferricferrocyanide, iron oxides, manganese violet, mica, red 27 lake, red 33,red 6 lake, titanium dioxide, ultramarines, yellow 5, yellow 6 lake,zinc oxide, and zinc stearate.

Emollients are supple, waxlike, lubricating, thickening substances whichare added to cosmetic/dermatological products to prevent water loss andhave a softening and soothing effect on the skin.

In some embodiments, emollients may include, but are not limited to,10-hydroxydecanoic acid, acetyl glyceryl ricinoleate, acetylated castoroil, acetylated hydrogenated cottonseed glyceride, acetylated lanolin,acetylated lanolin alcohol, acetylated palm kernel glycerides, agar,Ahnfeltia concinna extract, Ahnfeltia extract, Alaria esculenta, algaeextract, algin, almond oil, α-glucan oligosaccharide, amodimethicone,Anacystis nidulans extract, apricot kernel oil, arachidic acid,arachidonic acid, arachidyl alcohol, arachidyl propionate, Arachishypogaea extract, argan oil, artemia extract, Ascophyllum nodosum,Asparagopsis armata extract, Astrocaryum murumuru seed butter, avocadooil, babassu oil, batyl alcohol, beeswax, behentrimonium chloride,bis-diglyceryl polyacyladipate, bis-PEG-18 methyl ether dimethyl silane,borage seed oil, Borago officinalis extract, Borago officinalis seedoil, Brassica campestris, Butyrospermum fruit, Butyrospermum parkii,Buxus chinensis, C₁₀₋₃₀ cholesterol/lanosterol esters, C₁₂₋₁₅ alkylbenzoate, C₁₂₋₁₈ acid triglyceride, C₁₈₋₃₆ acid triglyceride, candelillawax, Cannabis sativa L. oil, caprylic/capric triglyceride, caprylylmethicone, carrot oil, Carthamus tinctorius oil, Carya illinoensis oil,castor isostearate succinate, castor oil, Caulerpa taxifolia extract,cephalin, cera microcristallina, cetearyl alcohol, cetearylethylhexanoate, cetearyl octanoate, cetyl acetate, cetyl alcohol, cetyldimethicone copolyol, cetyl esters, cetyl hydroxyethylcellulose, cetylpalmitate, chlorella, cholesterol, Chondrus crispus, cocoa butter,cocoglycerides, coconut oil, Cocus nucifera, Codium tomentosum extract,Corallina officinalis extract, corn oil, Corylus Americana, Corylusavellana, cyclohexasiloxane, cyclomethicone, cyclopentasiloxane,cyclotetrasiloxane, decyl oleate, dicaprylyl carbonate, diethylhexylcarbonate, diethylhexyl malate, diisopropyl adipate, diisopropyl dimerdilinoleate, diisostearoyl trimethylolpropane siloxy silicate,diisostearyl dimer dilinoleate, diisostearyl malate, dimer dilinoleyldimer dilinoleate, dimethicone, dimethi cone copolyol, dimethiconecrosspolymer, dimethicone/PEG-10/15 crosspolymer, Dimethiconol,dipentaerythrityl hexacaprylate/hexacaprate disodium diglycerylphosphate, disodium glyceryl phosphate, docosahexaenoic acid, Dromiceiusoil, dulse, Durvillaea antarctica extract, egg yolk, eicosapentaenoicacid, Elaeis guineensis, emu oil, Enteromorpha compressa extract, ethylmacadamiate, ethylhexyl palmitate, ethylhexyl stearate, Euphorbiacerifera wax, evening primrose oil, γ-linolenic acid (GLA), Gellidielaacerosa extract, glycereth-26, glycereth-26 phosphate, glycereth-6laurate, glycerol monostearate, glycerol triacetate, glycerol trioleate,glyceryl behanate, glyceryl cocoate, glyceryl dibehanate, glyceryldipalmitate, glyceryl distearate, glyceryl ester, glyceryl isopalmitate,glyceryl isostearate, glyceryl myristate, glyceryl oleate, glycerylpalmitate, glyceryl stearate, glyceryl stearate SE, Glycine soja oil,Glycine soja seed extract, Glycine soja sterols, glycol stearate,glycolipid, grape seed oil, Haslea ostrearia extract, hazelnut oil,Helianhtus annuus seed oil, Helianthus oil, hemp seed oil, hexyllaurate, hexyldecanol, Himanthalia elongate extract, hydrogenatedcoco-glyceride, hydrogenated lecithin, hydrogenated olive oil,hydrogenated palm glycerides, hydrogenated polydecene, hydrogenatedpolyisobutene, hydrogenated vegetable glycerides citrate, hydrolyzedjojoba esters, hydrolyzed jojoba protein, hydroxylated lecithin, Irishmoss extract, isononyl isononanoate, isopropyl isostearate, isopropyllanolate, isopropyl myristate, isopropyl palmitate, Japan wax, jojobabutter, jojoba esters, jojoba oil, jojoba wax, kelp extract, kukui nutoil, Laminaria longicruris, Laminaria saccharine, lanolin, lanolinalcohol, lauryl lactate, lecithin, linoleic acid, lupine, lupine oil,Lupinus albus extract, macadamia nut oil, Mangifera indica (mango) seedbutter, Mastocarpus stellatus, meadowfoam seed oil, methicone, methylglucose sesquistearate, methyl trimethicone, methylsilanol mannuronate,methylsilanol PEG-7 glyceryl cocoate, Microcystis aeruginosa, mineraloil, murumuru seed butter, myristyl myristate, neopentyl glycoldicaprylate/dicaprate, octyl palmitate, octyl stearate, octyldodecanol,octyldodecyl myristate, octyldodecyl neopentanoate, Oenothera biennisoil, Olea europaea fruit oil, Olea europaea oil unsaponifiables, oliveoil/olive fruit oil, Orbignya martiana, Orbignya oleifera, Oryza sativaoil, Padina pavonica extract, palm kernel acid, palm oil, Palmariapalmata extract, palmitic acid, Paraffinum liquidum, peanut oil, pecanoil, pectin, PEG 90M, PEG-10 dimethicone, PEG-10 dimethicone/vinyldimethicone crosspolymer, PEG-10 rapeseed sterol, PEG-100 stearate,PEG-12 dimethicone, PEG-20 methyl glucose sesquistearate, PEG-40hydrogenated castor oil, PEG-60 almond glycerides, PEG-60 hydrogenatedcastor oil, PEG-7 glyceryl cocoate, PEG-8, PEG/PPG-17/6 copolymer,PEG/PPG-18/18 dimethicone, PEG/PPG-20/15 dimethicone, pentaerythrityltetraoctanoate, Persea gratissima oil, petrolatum, phenyl trimethicone,phosphatidylcholine, phosphatidylethanolamine, phytosterol, pistachioseed oil, Pistacia vera seed oil, polyethylene, polyglycerolmonostearate, polyglyceryl 2 triisostearate, polyglyceryl-3methylglucose di stearate, polyglyceryl-4 isostearate, polyglyceryl-6isostearate, polymethylsilsesquioxane, PPG-3 benzyl ether myristate,propylene glycol isostearate, propylene glycol laurate, Prunus amygdalusdulcis, Prunus dulcis, pumpkin seed extract, quinoa oil, rapeseed oil,red algae, rice bran oil, rice oil, Ricinus communis, Rosa canina, Rosacentifolia, Rosa centifolia flower, Rosa eglanteria, Rosa mosqueta, Rosarubiginosa, rose hip, rose hip oil, rutin, saccharide isomerate,safflower seed oil, Sargassum filipendula extract, Seamollient, sesameoil, Sesamum indicum, sesquioleate, shea butter, silicone, siloxane,Simmondsia chinensis, sodium PEG-7 olive oil carboxylate, sodiumpolyacrylate, Sonojell, soy oil, soya sterol, spirulina, squalane,squalene, stearates, stearic acid, stearyl alcohol, stearyl methicone,sunflower seed oil, sweet almond, sweet almond oil, synthetic beeswax,Theobroma cacao seed butter, tribehenin, tribehenin PEG-20 esters,tricaprylin, tridecyl stearate, triethoxycaprylylsilane,triethoxysilylethyl polydimethylsiloxyethyl hexyl dimethicone,triglyceride, trihydroxystearin, triisocetyl citrate, trilaurin,trimethyl siloxy silicate, trioctanoin, trioctyldodecyl citrate,Triticum vulgare oil, Undaria pinnatifida, vitamin F, Vitis vinifera,walnut oil, wheat germ glycerides, wheat germ oil, and Ximenia americanaoil.

Film-Forming/Holding agents are substances which are added tocosmetic/dermatological products to help leave a pliable, cohesive, andcontinuous covering over the skin. This film has water-bindingproperties and leaves a smooth feel on skin.

In some embodiments, film-forming/holding agents may include, but arenot limited to, acrylate, acrylates copolymer, acrylates/C₁₀₋₃₀ alkylacrylate crosspolymer, acrylates/dimethicone copolymer, adipicacid/neopentyl glycol/trimellitic anhydride copolymer, allylmethacrylates crosspolymer, carnauba wax, cellulose gum, Coperniciacerifera wax, dextrin, diisopropyl adipate, glyceryl polymethacrylate,hydrolyzed wheat protein, hydroxyethylcellulose, locust bean, neopentylglycol diheptanoate, PEG-40 hydrogenated castor oil, polyacrylamide,polyacrylate-17, polyglucuronic acid, polyglyceryl methacrylate,polyisobutene, polymethyl methacrylate, polyquaternium-10,polyquaterniums, polyvinyl alcohol, polyvinylpyrrolidone, propylenecarbonate, PVM/MA (polyvinyl methyl ether/maleic acid) decadienecrosspolymer, PVP [poly(vinylpyrrolidone)] copolymer,PVP/dimethylaminoethyl-methacrylate, sodium carbomer, sodiumpolyacrylate, styrene/acrylates copolymer, triethoxycaprylylsilanecrosspolymer, VA (vinyl acetate)/crotonates, VA/crotonates copolymer, VP(vinylpyrrolidone)/eicosene copolymer, and VP/hexadecene copolymer.

Fragrance ingredients are a single or a blend of volatile and/orfragrant plant oils (or synthetically derived oils) that impart aromaand odor to cosmetic/dermatological products. The level of fragrance touse varies according to the product type. In some embodiments, a facecream may contain about 0.01% fragrance by weight.

In some embodiments, fragrances (e.g, synthetic and fragrant plantextracts) may include, but are not limited to, Acacia farnesianaextract, Aerocarpus santalinus, amyl cinnamate, amyl salicylate, amyrisoil, Anethum graveolens, Angelica archangelica root oil, anisaldehyde,anise, balm mint extract, balsam peru, bay leaf oil, bergamot oil,bitter orange flower, bois de rose oil, bois oil, Boswellia carterii,butylphenyl methylpropional, cananga extract, Cananga odorata, cardamom,cedarwood, cherry extract, Citrus aurantifolia, Citrus aurantium, Citrusaurantium extract, Citrus medica limonium, clary oil, Commiphora myrrhaextract, coriander, Cucurbitea peponis, cyclamen aldehyde, dill extract,ethyl vanillin, eugenol, farnesol, farnesyl acetate, Ferula galbaniflua,fir needle oil, floralozone, Foeniculum vulgare extract, frankencenseextract, galbanum, Gardenia florida extract, grapefruit oil, guaiacwood, Guaiacum officinale, hedione, hexyl cinnamal, hyssop, Illiciumvernum, Iris florentina extract, jasmine oil, Jasminium grandiflorum,jonquil extract, Laurus nobilis, lauryl lactate, lavandin oil, Lavandulaangustifolia, Lavandula officinalis, lavender extract and oil, lemon,lemon balm, lemongrass oil, Levisticum officinale root extract, lime oiland extract, limonene, linalool, Litsea cubeba, mandarin orange oil orextract, marjoram, Melissa officinalis, Mentha piperita, Mentha spicata,Mentha viridis, menthol, menthone, menthoxypropanediol, menthyl lactate,methyldihydrojasmonate, mimosa oil or extract, mint, Narcissus poeticuswax, neroli, neroli oil, olibanum extract, orange blossom, orchid,Origanum majorana, orris root, patchouli, pentadecalactone, petitgrainmandarin, Pogostemon cablin, Rosa damascena oil, Rosa gallica flowerextract, rose flower, rose flower oil, rose oil, rosemary extract,rosemary oil, rosewood oil, sandalwood oil, Santalum album seed extract,sausurrea oil, sclareolide, spearmint oil, star anise, tangerine oil,Thymus vulgaris oil, Vanilla planifolia fruit extract, verbena extract,vetiver oil or extract, and ylang ylang.

Exfoliation involves the removal of the oldest dead skin cells on theskin's outermost surface and can be achieved through mechanical orchemical means. Mechanical exfoliation involves the use of scrub agentsor body polishers which are solid materials from natural origins (finepowder of seeds or shells of different vegetables), or are obtained bychemical synthesis (tiny beads of styrene or polyethylene). Scrub agentcontaining cosmetic/dermatological products are used to removesuperficial skin stratum corneum (horny layer) by mechanical abrasion,leaving behind a fresh, smooth skin surface. Scrub agents are selectedbased on the body part to be treated. Chemical exfoliants are oftenreferred to as leave-on exfoliants. Leave-On Exfoliant ingredients aresubstances which are added to cosmetic/dermatological products to give asubject a low concentration of acid on a daily basis. They are usuallyapplied after cleansing and are for oily, acne-prone and sun-damagedskin. They may also help with lightening discoloration areas and withscarring.

In some embodiments, leave-on exfoliants may include, but are notlimited to, α-hydroxy acids (AHA) (such as glycolic acid, lactic acid,malic acid, citric acid, hydroxycaprylic acid, hydroxycapric acid andtartaric acid), ammonium glycolate, amygdalic acid, Ananas sativus fruitextract, β-hydroxy acids (BHA) (such as salicylic acid, β-hydroxybutyricacid, tropic acid and trethocanic acid), bromelain, mandelic acid,papain, papaya extract, pawpaw extract, pineapple extract, polyhydroxyacid (PHA) such as gluconolactone and lactobionic acid, and urea.

In some embodiments, prescription drugs may include, but are not limitedto, adapalene (Differin®, Teva, Pimpal®, Gallet, Adaclene, Adapen™,Adeferin™) all-trans retinoic acid (Tretinoin, Aberela®, Airol®, A-Ret™,Atralin®, Avita®, Retacnyr, Refissa®, Renova®, RetinA®, Retino-A*,ReTrieve®, or Stieva-A™), aminophylline (Aminophyl, Procellix,Phyllocontin®, Celluthin, Cellulean®, azelaic acid (AzClear Action,Azelex®, SynCare, Finacea®, Finevin®, Skinoren®, Melazepam, Azelex®,Azaclear®, Aziderm®), bimatoprost (Lumigan®), Latisse®, hydroquinone(LustraAF®, Unblemish, Lustra °, Sunvanish™, PCA Pigment Gel °,Sledgehammer™), isotretinoin (Accutane®, Roaccutane®, Amnesteem®,Claravis™, Absorica™, Isotroin, Epuris™) Sotret®, and Tazarotene(Tazorac®, Avage®, Zorac®, and Fabior™).

Preservatives are substances which prevent bacterial, microbial orfungal contamination of cosmetic/dermatological products therebyincreasing the product's shelf life and consumer safety. Some of theseagents also have stabilizing effects able to preserve the function ofvarious active ingredients including anti-oxidants (vitamins),emulsifiers and surfactants.

In some embodiments, preservatives may include, but are not limited to,1,2-hexanediol, benzoic acid, benzothonium chloride, borax, bronopol,butylparaben, caprylyl glycol, chlorophene, chloroxylenol,chlorphenesin, dehydroacetic acid, diazolidinyl urea, DMDM hydantoin,ethylhexylglycerin, ethylparaben, formaldehyde-releasing preservative,Germaben II, hoelen, imidazolidinyl urea, iodopropynyl butyl carbamate,isobutylparaben, methyl chloroisothiazolinone, methyl dibromoglutaronitrile, Methyl isothiazolinone, methylparaben, o-cymen-5-ol,phenoxy ethanol, phenoxyisopropanol, phytosphingosine, polyaminopropylbiguanide, potassium sorbate, propylparaben, quaternium-15, sodiumbenzoate, sodium citrate, sodium dehydroacetate, sodiumhexametaphosphate, sodium hydroxymethylglycinate, sodium lactobionate,sodium metabisulfite, sodium sulfite, sorbic acid, and styrax benzoin.

In some embodiments, scrub agents may include, but are not limited to,alumina, aluminum silicate, apricot kernel, azuki beans, diatomaceousearth, polyethylene, polyethylene glycol (PEG), sea salt, sodiumchloride, and walnut-shell powder.

Silicone ingredients are substances which are added tocosmetic/dermatological products to create a silky-like feel on theskin, impart emolliency, and be a water-binding agent that holds upwell, even when skin becomes wet. Silicones also act as skin protectant,conditioner, pearlizer, film-former, moisturizer, thickener, andemulsifier. As silicones are very mild, they are often used to reduceirritation of harsh surfactants. Some cosmetic/dermatologicalcompositions can be used for wound healing and for improving theappearance of scars [Journal of Wound Care (2000), 9(7), 319-324].

In some embodiments, silicones may include, but are not limited to,acrylates/dimethicone copolymer, amodimethicone, bis-PEG-18 methyl etherdimethyl silane, bis-phenylpropyl dimethicone, caprylyl methicone, cetyldimethicone, cetyl dimethicone copolyol, cetyl PEG/PPG-10/1-dimethicone,diisostearoyl trimethylolpropane siloxy silicate, dimethicone,dimethicone copolyol, dimethicone crosspolymer, dimethicone/PEG-10/15crosspolymer, dimethicone/vinyl dimethicone crosspolymer, dimethiconol,isopropyl titanium triisostearte/triethoxycaprylylsilane crosspolymer,methicone, methyl trimethicone, methylsilanol mannuronate, methylsilanolPEG-7 glyceryl cocoate, PEG-10 dimethicone, PEG-10 dimethicone/vinyldimethicone crosspolymer, PEG-12 dimethicone, PEG/PPG-18/18 dimethicone,PEG/PPG-20/15 dimethicone, phenyl trimethicone,polymethylsilsesquioxane, polysilicone-11, silica dimethyl silylate,silicone, siloxane, simethicone, stearyl dimethicone, stearyl methicone,triethoxycaprylylsilane, triethoxycaprylylsilane crosspolymer,trimethylsiloxysilicate, and vinyl dimethicone/methicone silsesquioxanecrosspolymer.

The term “skin-identical agents” or “skin-repairing agents” refers tothe substances between skin cells (technically referred to as theintercellular matrix) that keep skin cells connected and help maintainskin's fundamental external structure. They can be added to thecompositions provided herein to help keep the skin moisturized andhydrated without causing unnecessary inflammation or irritation.

In some embodiments, skin-identical/repairing agents may include, butare not limited to, acetyl hexapeptide-3, acetyl octapeptide-3, adenine,aquaporins, aspartic acid, β-sitosterol, Butyrospermum parkii, Buxuschinensis, canola oil, carrot oil, ceramide 1, ceramide 2, ceramide 3,ceramide 6-II, cetearyl octanoate, cholesterol, chondroitin sulfate,creatine, cysteine, cysteine, decylene glycol, dextran,dimethylaminoethanol (DMAE), elastin, fibronectin, fructose, glucose,glutamine, glycerin, glycerine, glycerol, glycine, glycogen, glycolipid,glycosaminoglycans, glycosphingolipid, hyaluronic acid, hydrogenatedpalm glycerides, hydrolyzed glycosaminoglycans, hydroxyproline,inositol, isoleucine, jojoba oil, jojoba wax, lactobionate, lanolin,lanolin alcohol, lecithin, leucine, lysine, Mangifera indica (mango)seed butter, melibiose, methionine, milk protein, mucopolysaccharide,N-acetyl-L tyrosine, natural moisturizing factor (NMF), Olea europaeafruit oil, Olea europaea oil unsaponifiables, olive oil/olive fruit oil,palm oil, palmitic acid, palmitoyl oligopeptide, phenylalanine,phosphatidylcholine, phosphatidylethanolamine, phospholipid,phytosphingosine, polysaccharide, proline, pumpkin seed extract, RNA,saccharide isomerate, saccharides, Saccharomyces cerevisiae, serine,Simmondsia chinensis, sodium chondroitin sulfate, sodiumdilauramidoglutamide lysine, sodium hyaluronate, sodium pyrrolidonecarboxylic acid (PCA), sphingolipids, squalane, squalene, stearates,stearic acid, sucrose, thiotaurine, threonine, tribehenin,trihydroxystearin, tryptophan, urea, valine, and wheat protein.

The term “slip agent” is used to describe a range of ingredients whichcan help other ingredients spread over the skin and penetrate into theskin. Slip agents can also have humectant (hygroscopic) properties.

In some embodiments, slip agents may include, but are not limited to,amodimethicone, bis-PEG-18 methyl ether dimethyl silane,bis-phenylpropyl dimethicone, butylene glycol, cetyl dimethicone, cetyldimethicone copolyol, cetyl PEG/PPG-10/1-dimethicone, cyclohexasiloxane,cyclomethicone, cyclopentasiloxane, cyclotetrasiloxane, decylene glycol,diisostearoyl trimethylolpropane siloxy silicate, dimethicone,dimethicone copolyol, dimethicone crosspolymer, dimethiconol,dipropylene glycol, hexylene glycol, hydrolyzed silk, isododecane,methicone, methyl trimethicone, methylsilanol mannuronate, methylsilanolPEG-7 glyceryl cocoate, Good, PEG-10 dimethicone, PEG-10dimethicone/vinyl dimethicone crosspolymer, PEG-12 dimethicone,PEG/PPG-18/18 dimethicone, PEG/PPG-20/15 dimethicone, pentylene glycol,phenyl trimethicone, polymethylsilsesquioxane, PPG-3 benzyl ethermyristate, silica dimethyl silylate, silk powder, siloxane, simethicone,sorbitol, stearyl dimethicone, stearyl methicone,triethoxycaprylylsilane, trimethylsiloxysilicate, xylitol, and zincstearate.

Sunscreen actives are substances which are added tocosmetic/dermatological products to protect the skin against UV rays.They can be organic molecules which absorb high-energy ultraviolet raysand release the energy as lower-energy rays, thereby preventing theskin-damaging ultraviolet rays from reaching the skin. They can beinorganic particulates that reflect, scatter, and absorb UV light. Theycan also be organic particulates that mostly absorb light like organicchemical compounds, but contain multiple chromophores, may reflect andscatter a fraction of light like inorganic particulates, and behavedifferently in formulations than organic chemical compounds.

In some embodiments, sunscreen actives may include, but are not limitedto, avobenzone, benzephenone-3, benzophenones, bumetrizole, butylmethoxydibenzoylmethane, ecamsule, ensulizole, ethylhexylmethoxycinnamate, homosalate, menthyl anthranilate, meradmiate, MexorylSX, octinoxate, octisalate, octocrylene, octyl methoxycinnamate, octylsalicylate, oxybenzone, padimate O, para-aminobenzoic acid (PABA),Parsol 1789, terephthalylidine dicamphor sulfonic acid, Tinosorb M,Tinosorb S, and titanium dioxide.

Emulsifiers are substances which are added to cosmetic/dermatologicalproducts to help keep unlike ingredients (such as oil and water) fromseparating in an emulsion. There are 2 types of emulsifiers.Oil-in-water (o/w) emulsifiers keep oil drops packed in water, whilewater-in-oil (w/o) emulsifiers keep water drops packed in oil. W/Oemulsifiers are used for a fatty feel (e.g. night & sun protectioncreams). O/W emulsifiers are used more in moisturizing products (e.g.body lotions, day creams).

Surfactants are substances which are added to cosmetic/dermatologicalproducts to degrease and emulsify oils and fats and suspend soil,allowing them to be washed away, as laundry products do. They aresometimes refer to as “detergent cleansing agents.” Based on theircleansing power surfactants are classified into primary and secondary orco-surfactants. Based on the chemical structure there are anionic,amphoteric, non-ionic, and quaternary agents. Surfactants form the baseof all personal cleansing products and can also have wetting,conditioning, defatting, emulsifying, & thickening effects.

In some embodiments, emulsifiers, surfactants, and detergents mayinclude, but are not limited to, ammonium laureth sulfate, ammoniumlauryl sulfate, arachidyl glucoside, behenic acid, bis-PEG-18 methylether dimethyl silane, C₂₀₋₄₀ pareth-40, cocamidopropyl betaine,cocamidopropyl dimethylamine, cocamidopropyl hydroxysultaine,coco-glucoside, coconut oil, decyl glucoside, dicetyl phosphate,dihydrocholeth-30, disodium cocoamphodiacetate, disodium cocoylglutamate, disodium lauraminopropionate, glyceryl behanate, hydrogenatedvegetable glycerides citrate, isohexadecane, isostearamide DEA,lauramphocarboxyglycinate, laureth-23, laureth-4, laureth-7, laurylPEG-9 polydimethylsiloxyethyl dimethicone, lauryl alcohol, laurylglucoside, magnesium laureth sulfate, magnesium oleth sulfate, myristicacid, nonoxynols, oleic acid, oleth 10, palm kernel acid, palmitic acid,PEG-60 almond glycerides, PEG-75 shea butter glycerides, PEG 90M, PEG-10dimethicone, PEG-10 dimethicone/vinyl dimethicone crosspolymer, PEG-10rapeseed sterol, PEG-100 stearate, PEG-12 dimethicone, PEG-120 methylglucose dioleate, PEG-20 methyl glucose sesquistearate, PEG-40 stearate,PEG-60 hydrogenated castor oil, PEG-7 glyceryl cocoate, PEG-8, PEG-80sorbitan laurate, PEG/PPG-17/6 copolymer (polyethyleneglycol/polypropylene glycol-17/6 copolymer), PEG/PPG-18/18 dimethicone,PEG/PPG-20/15 dimethicone, poloxamer 184, Poloxamer 407, poloxamers,polyglyceryl-3 beeswax, polyglyceryl-4 isostearate, polyglyceryl-6isostearate, polysorbate 20, polysorbate 60, polysorbate 80, potassiumcetyl phosphate, potassium hydroxide, potassium myristate, PPG-12buteth-16, PPG-26-Buteth-26, Salvia officinalis, Saponaria officinalisextract, soapwort, sodium C₁₄₋₁₆ olefin sulfonate, sodium cetearylsulfate, sodium cocoamphoacetate, sodium cocoate, sodium cocoylglutamate, sodium cocoyl isethionate, sodium dilauramidoglutamidelysine, sodium hexametaphosphate, sodium hydroxide, sodium laurethsulfate, sodium laureth-13 carboxylate, sodium lauroamphoacetate, sodiumlauroyl lactylate, sodium lauroyl sarcosinate, sodium lauryl glucosecarboxylate, sodium lauryl sulfate, sodium methyl cocoyl taurate, sodiummethyl taurate, sodium myreth sulfate, sodium palm kernelate, sodiumpalmate, sodium PEG-7 olive oil carboxylate, sodium trideceth sulfate,steareth-20, TEA-lauryl sulfate (triethanolamine-lauryl sulfate), andtribehenin PEG-20 esters.

Thickeners are substances which are added to cosmetic/dermatologicalproducts to enhance the consistency, volume and viscosity of cosmeticproducts, thereby providing more stability and better performance. Whilesome thickeners have also emulsifying or gelling properties, themajority of thickeners have the ability to retain water on the skin andact therefore as moisturizers. Thickeners can be completely natural likewaxes but also synthetic or semi-synthetic.

In some embodiments, thickeners may include, but are not limited to,Acacia senegal, acetyl glyceryl ricinoleate, acetylated castor oil,acetylated hydrogenated cottonseed glyceride, acetylated palm kernelglycerides, acrylates/steareth-20 methacrylate copolymer, agar,Ahnfeltia concinna extract, Ahnfeltia extract, Alaria esculenta, algae,algae extract, algin, alkyloamides, Althaea rosea, Althea officinalis,alumina, aluminum hydroxide, aluminum stearate, ammoniumacryloyldimethyltaurate/VP copolymer, Anacystis nidulans extract,arachidic acid, arachidonic acid, arachidyl alcohol, arachidylpropionate, arrowroot, artemia extract, Ascophyllum nodosum, ascorbylmethylsilanol pectinate, Asparagopsis armata extract, beeswax, behenicacid, behentrimonium chloride, behenyl alcohol, bis-diglycerylpolyacyladipate, bismuth oxychloride, C₁₂₋₁₅ alkyl benzoate, C₁₂₋₁₈ acidtriglyceride, C₁₃₋₁₄ isoparaffin, C₁₈₋₃₆ acid triglyceride, candelillawax, caprylic/capric triglyceride, carbomer, carbopol, carnauba wax,carrageenan, Caulerpa taxifolia extract, cellulose, Cellulose gum,cephalin, Cera alba, ceresin, ceteareth-20, cetearyl alcohol, cetearylethylhexanoate, cetearyl glucoside, cetearyl octanoate, cetyl alcohol,cetyl dimethicone copolyol, cetyl hydroxyethylcellulose, cetylpalmitate, cetyl PEG/PPG-10/1-dimethicone, Chlorella, Chondrus crispus,cocamide DEA and MEA, cocoglycerides, Codium tomentosum extract,Copernicia cerifera wax, Corallina officinalis extract, Cyamopsistetragonoloba, DEA oleth-10 phosphate, diethanolamine (DEA), di-PPG-3myristyl ether adipate, dimethicone crosspolymer, dimethicone/vinyldimethicone crosspolymer, dimer dilinoleyl dimer dilinoleate,dipentaerythrityl hexacaprylate/hexacaprate, disodium diglycerylphosphate, disodium glyceryl phosphate, docosahexaenoic acid, dulse,Durvillaea antarctica extract, eicosapentaenoic acid, Enteromorphacompressa extract, erythropoietin (Epo), ethyl macadamiate, ethylhexylstearate, Euphorbia cerifera wax, fuller's earth, gelatin, Gellidielaacerosa extract, glycereth-26, glycereth-26 phosphate, glycereth-6laurate, glycerol monostearate, glycerol triacetate, glycerol trioleate,glyceryl behanate, glyceryl cocoate, glyceryl dipalmitate, glyceryldistearate, glyceryl isopalmitate, glyceryl isostearate, glycerylmyristate, glyceryl oleate, glyceryl palmitate, glycerylpolymethacrylate, glyceryl stearate, glyceryl stearate SE, glycolstearate, glycolipid, guar gum, guar hydroxypropyltrimonium chloride,gums, Haslea ostrearia extract, hepatocyte growth factor (HGF),Himanthalia elongate extract, hydrogenated coco-glyceride, hydrogenateddidecene, hydroxyethyl acrylate/sodium acryloyldimethyl tauratecopolymer, hydroxyethylcellulose, hydroxypropyl guar, hydroxypropylstarch phosphate, interleukin (IL), Irish moss extract, isohexadecane,isoparaffin, isopropyl lanolate, isopropyl myristate, isopropylpalmitate, isopropyl titanium triisostearte/triethoxycaprylyl silanecrosspolymer, isostearami de DEA, isostearic acid, Japan wax, kelpextract, Laminaria digitata, Laminaria longicruris, Laminariasaccharine, laureth-23, laureth-4, laureth-7, lauryl PEG-9polydimethylsiloxyethyl dimethicone, lithium magnesium sodium silicate,locust bean, magnesium aluminum silicate, magnesium stearate, magnesiumsulfate, mallow, marshmallow, Mastocarpus stellatus, monoethanolamine(MEA), microcrystalline wax, Microcystis aeruginosa, montan wax,myristyl myristate, neopentyl glycol dicaprylate/dicaprate, neopentylglycol diheptanoate, nylon-12, octyl palmitate, octyl stearate,octyldodecanol, octyldodecyl myristate, oleic acid, oleth 10, ozokerite,Padina pavonica extract, Palmaria palmata extract, palmitoylhexapeptide-12, palmitoyl oligopeptide, palmitoyl pentapeptide-3,palmitoyl tetrapeptide-7, palmitoyl tripeptide-5, paraffin, pectin,PEG-100 stearate, PEG-150 distearate, PEG-32, PEG-40 hydrogenated castoroil, pentaerythrityl tetraisostearate, pentaerythrityl tetraoctanoate,polybutene, polyethylene, polyethylene glycol, polyglycerolmonostearate, polyglyceryl 2 triisostearate, polyglyceryl-3 beeswax,polyglyceryl-3 methylglucose distearate, polyisobutene, polysorbate 20,polysorbate 60, polysorbate 80, polysorbates, PPG-12 buteth-16, PPG-2myristyl ether propionate, propylene glycol isostearate, propyleneglycol stearate, pullulan, pumpkin seed extract, PVM/MA decadienecrosspolymer, Pyrus cydonia, Pyrus malus, quaternium-18 hectorite,quince seed, red algae, ricinoleate, Salvia officinalis, Sargassumfilipendula extract, sclerotium gum, Seamollient, seaweed, sesquioleate,silent information regulator two proteins (sirtuins), silica, silicate,sodium acrylate/acryloydimethyl taurate copolymer, sodium carboxymethyl3-glucan, sodium hexametaphosphate, sodium lauroyl lactylate, sodiumlauryl sulfate, sodium polyacrylate, Solanum tuberosum extract, sorbitanoleate, sorbitan sesquioleate, sorbitan stearate, sorbitol, spirulina,stearic acid, stearyl alcohol, subtilisin, synthetic beeswax, TEA-laurylsulfate, titanium dioxide, tragacanth, transforming growth factor (TGF),tribehenin, tridecyl stearate, tridecyl trimellitate, triglyceride,trigonella foenum-graecum seed extract, trihydroxystearin, trilaurin,tripeptide-32, trioctanoin, Undaria pinnatifida, vascular endothelialgrowth factor (VEGF), vinyl dimethicone/methicone silsesquioxanecrosspolymer, wheat germ glycerides, xanthan gum, xylitol, zinc oxide,and zinc stearate.

In some embodiments, penetration enhancers can be used to aid thecompounds or compositions provided herein in passing through the outlater (epidermis) of the skin and into the dermis and/or hypodermis ofthe skin. Penetration enhancers may selected from one of the followingclasses of compounds:

-   -   1. Fatty alcohols, fatty acids and related compounds.    -   2. Biologics such as lecithins, phospholipids.    -   3. Amines and amides.    -   4. Complexing agents such as cyclodextrins.    -   5. Surfactants including Brij, tweens, spans, and pluronics.    -   6. N-methyl pyrrolidone and related compounds.    -   7. Ionic compounds such as ascorbate and sodium hyaluronate.    -   8. Dimethyl sulfoxide and related compounds.    -   9. Solvents such as ethanol, acetone, glycols, glycerols,        squalene, tween 20, etc.    -   10. Azone and related compounds.

The cosmetic or dermopharmaceutical compositions provided herein caninclude cleansers, facial masks, toners, moisturizers, sunscreen,tanning oils and lotions, skin lighteners, serums, and exfoliants.

In addition, various adjuvants such as are commonly used in the art canbe included. These and other such compounds are described in theliterature, e.g., Rowe, R. C.; Sheskey, P. J. & Quinn, M. E. (Eds.).(2009). Handbook of Pharmaceutical Excipients. London Chicago:Pharmaceutical Press; Hoepfner E., et al. (2002). Fiedler Encyclopediaof Excipients for Pharmaceuticals, Cosmetics and Related Areas,Aulendorf, Germany: Cantor; Kemper, F. H., et al. (2000). Blue ListCosmetic Ingredients, Aulendorf, Germany: Cantor; and Smolinske, S. C.(1992). Handbook of Food, Drug and Cosmetic Excipients, Boca Raton, FL:CRC Press.

Ingredients, additives, products or materials, and adjuvants, which canbe employed in the compositions discussed herein are referred to bytheir commonly used chemical names or by the international nomenclature,(recognized by the European Union), commonly referred to as INCI namegiven them in any edition of the International Cosmetic IngredientDictionary and Handbook, (hereafter INCI Dictionary), or in any editionof the International Buyers' Guide, all published by the Personal CareProducts Council (PCPC), Washington DC Numerous commercial suppliers ofmaterials listed by INCI name, trade name, or both, can be found in anyedition of the INCI Dictionary and in numerous commercial tradepublications.

Cosmetic or dermopharmaceutical compositions provided herein can beadministrated to any skin type including normal skin, dry skin, oilyskin, combination skin (a combination of both oily and dry or normalskin, e.g. certain areas of the face are oily and the others dry),sensitive skin, and acne prone skin.

The term “administration” or “administering” refers to a method ofproviding a dosage of a compound or cosmetic or dermopharmaceuticalcomposition to a subject, where the method is epicutaneous (topical) orsubcutaneous. Modes of administration, dosing schedules disclosedcompounds and compositions can be determined according to the criteriagenerally taken into account in the establishment of a cosmetic and/ordermatological treatment adapted to, for example, a patient's type ofskin. The compositions can be administered such that they cover theentire area to be treated.

As used herein, “topical use” and “topically applying” means directlylaying on or spreading on the skin, hair, or nail, e.g., by use of thehands or an applicator such as a wipe.

The term “topical composition” as used herein refers to any compositionsuitable for the topical application to mammalian keratinous tissue suchas in particular to human skin. In particular, the topical compositionsaccording to the present disclosure are cosmetic compositions that canbe topically applied to mammalian keratinous tissue, particularly tohuman skin.

The term “dermatologically acceptable” is used to refer to compounds andcompositions that retain biological effectiveness and which are suitablefor use in contact with the skin or hair of humans and lower animalswithout undue toxicity, incompatibility, instability, irritation,allergic response, and the like.

The term “dermatologically acceptable carrier”, “dermatologicallyacceptable diluent” or “dermatologically acceptable excipient” are wellknown in the art and are selected based on the end use application andrefer to a non-toxic, inert, and/or physiologically compatiblecomposition component. Except insofar as any conventional media or agentis incompatible with the active ingredient, its use in the cosmetic anddemorpharmaceutical compositions is contemplated.

The term “dermatologically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds providedherein and, which are suitable for use in contact with the skin or hairof humans and lower animals without undue toxicity, incompatibility,instability, irritation, allergic response, and the like. Non-limitingexamples include, but are not limited to, acetate, benzenesulfonate,benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate,carbonate, chloride, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, glyceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate, methylbromide,methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate,tosylate and triethiodide. Cosmetically acceptable basic/cationic saltsinclude, and are not limited to aluminum, benzathine, calcium,chloroprocaine, choline, diethanolamine, ethylenediamine, lithium,magnesium, meglumine, potassium, procaine, sodium and zinc. Other saltsmay, however, be useful in the preparation of compounds according tothis disclosure or of their dermatologically acceptable salts. Organicor inorganic acids also include, but are not limited to, hydriodic,perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic,hydroxy ethane sulfonic, oxalic, 2-naphthalenesulfonic,p-toluenesulfonic, cyclohexanesulfamic, saccharinic, and trifluoroaceticacid.

Administration of the compounds disclosed herein or the dermatologicallyacceptable salts thereof can be via any of the accepted modes ofadministration for agents that serve similar utilities including, butare not limited to, topically, intravaginally, rectally, intranasally,intralesionally, auricularly, conjunctivaly, by irrigation, andoropharyngeally.

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV for topical delivery is about 1.0 μg/cm² toabout 100 μg/cm².

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV for topical delivery is about 1.5 μg/cm² toabout 95 μg/cm².

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV for topical delivery is about 2.0 μg/cm² toabout 85 μg/cm².

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV for topical delivery is about 2.5 μg/cm² toabout 75 μg/cm².

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV for topical delivery is about 5 μg/cm² toabout 50 μg/cm².

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV for topical delivery is about 10 μg/cm² toabout 25 μg/cm².

In some embodiments, the compositions are provided in unit dosage formssuitable for single administration.

In some embodiments, the compositions are provided in unit dosage formssuitable for twice a day administration.

In some embodiments, the compositions are provided in unit dosage formssuitable for three times a day administration.

The present disclosure is also directed to a composition comprising upto 75% by weight of a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig,Ih, Ii, II, IIa, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/orIV, or a combination thereof.

In some embodiments, a composition can comprise about 0.01 to about 10%of the compound in solution.

In some embodiments, the composition will comprise about 0.01 to about5% of the compound in solution.

In some embodiments, the composition will comprise about 0.01 to about1% of the compound in solution.

In some embodiments, the composition will comprise about 0.05 to about0.5% of the compound in solution.

In some embodiments, the composition will comprise about 0.05 to about0.2% of the compound in solution.

In some embodiments, the composition will comprise about 0.05 to about0.15% of the compound in solution.

In some embodiments, the composition will comprise about 0.1 to about0.45% of the compound in solution.

In some embodiments, the composition will comprise about 0.1 to about0.25% of the compound in solution.

In some embodiments, the composition will comprise about 0.1 to about0.2% of the compound in solution.

In some embodiments, the composition will comprise about 0.15 to about0.40% of the compound in solution.

In some embodiments, the composition will comprise about 0.15 to about0.25% of the compound in solution.

In some embodiments, the composition will comprise about 0.15 to about0.20% of the compound in solution.

In some embodiments, the composition will comprise about 0.2 to about0.35% of the compound in solution.

In some embodiments, the composition will comprise about 0.25 to about0.3% of the compound in solution.

It is to be noted that concentrations and dosage values may also varydepending on the specific compound and the severity of the condition tobe alleviated. It is to be further understood that for any particularsubject, specific dosage regimens can be adjusted over time according tothe individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the concentration ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedcompositions.

Provided herein are compositions comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV that canbe used to improve the condition and aesthetic appearance of skin.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to alter the aesthetic appearance of skin associated with oraffected by skin aging.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to alter the aesthetic appearance of skin associated with oraffected by environmental damage to the skin.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to alter the aesthetic appearance of skin associated with oraffected by one or more of wrinkles, dry skin, sensitive skin, ordermatological symptoms caused by ineffective homeostatic regulation ofhealthy skin.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to alter the aesthetic appearance of skin associated with oraffected by, or treating or preventing, a skin condition/disorder (e.g.,a skin condition/disorder accompanied with a loss of skin elasticity).

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to improve the barrier function and viability of the skin.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, Ma, IIIb, IIIc, IIId, and/or IV can beused to alter the aesthetic appearance of skin associated with oraffected by wrinkling, sagging, and/or a loss of skin elasticity.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to alter the aesthetic appearance of skin associated with oraffected by, or treating or preventing, acne. For example, the acne canbe selected from one or more of simple acne, comedonic acne,papulopustular acne, papulocomedonic acne, nodulocystic acne, acneconglobata, cheloid acne of the nape of the neck, recurrent miliaryacne, necrotic acne, neonatal acne, occupational acne, acne rosacea,senile acne, solar acne or medication-related acne.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to alter the aesthetic appearance of skin associated with oraffected by deteriorations in skin viscoelasticity.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to alter the aesthetic appearance of skin associated with oraffected by one or more of wrinkles and/or fine lines, wizened skin, alack of elasticity and/or of tonus of the skin, thinning of the dermis,degradation of collagen fibers, flaccid skin, thinned skin, and theinternal degradation of the skin following exposure to ultravioletradiation.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to decrease the appearance of fine lines and/or wrinkles in theskin.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to create a more youthful appearance of the skin.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to decrease the appearance of bags and/or rings around the eyes.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to reduce the appearance of hyperpigmentation.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to increase or restore elasticity, resiliency, and/or suppleness ofthe skin.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to improve or increase one or more of the thickness, elasticity,flexibility, radiance, glow, and plumpness of the skin. The methodcomprising administering to a subject an effective amount of a compoundaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to improve the fineness of skin texture.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to improve the appearance of wrinkled, lined, dry, flaky, aged orphotodamaged skin.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to alter the aesthetic appearance of skin associated with oraffected by skin discolorations.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to whiten, lighten, and/or bleach the skin.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to alter the aesthetic appearance of skin associated with oraffected by, or treat or prevent, hyperpigmentation.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to alter the aesthetic appearance of skin associated with oraffected by, or treat or prevent, photodamaged skin.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to treat or prevent pigment deposition in the skin caused by UVexposure.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to treat or prevent vitiligo (skin condition in which there is aloss of brown color (pigment) from areas of skin).

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to treat or prevent a wound healing disorder in a mammal. Forexample, a compound or composition provided herein can be used as amedicament for preventing and/or treating a bedsore in a mammal.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to promote proliferation and/or mobility of skin keratinocyteand/or dermis fibroblasts (e.g., to increase skin regeneration).

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to improve epidermal cell repair activity, for example, in a human.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to increase fibroblast proliferation, keratinocyte proliferation,and/or expression of collagen.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to reduce collagenase activity.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to improve the thickness of the epidermis.

In one embodiment, a composition comprising one or more compoundsaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can beused to inhibit melanin production.

In some embodiments, the compositions are cosmetic compositions.

In some embodiments, the compositions are dermopharmaceuticalcompositions.

Also provided herein are kits. Typically, a kit includes one or morecompounds or compositions as described herein. In certain embodiments, akit can include one or more delivery systems, e.g., for delivering oradministering a compound as provided herein, and directions for use ofthe kit (e.g., instructions for treating a patient).

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications, and other publications are incorporated byreference in their entirety.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

EXAMPLES Example 1

This example demonstrates the anti-aging benefits of compounds of thecurrent disclosure on human female subjects.

Three groups of women were recruited to evaluate and compare theefficacy of three anti-aging test products (targeting the periorbitaleye area) intended to reduce the appearance of fine lines, wrinkles inthe outer canthus of the eyes (crow's feet area) over a 12 week period.Wrinkle assessment was conducted instrumentally using a Visioscan imageanalysis system. Effectiveness of the test product was evaluated usingpanelist self-assessment via questionnaire responses comprised of 3-4questions (Q1, Q2, Q3 & Q4). Each stage in the progression of treatmentswas photographically documented using a High Resolution ScientificallyMatched Photography technique. Image analysis was utilized to quantifychanges in fine lines and crow's feet condition observed in theScientifically Matched Photographs.

Subject Selection:

-   -   Number: Six subjects (two per group) to complete the study.    -   Sex: Females    -   Race: Caucasian/Asian/Hispanic    -   Age Range: 40 through 60 years old

Test samples:

-   -   Topical 0.15% of Compound #222 in Oil (a 50/50 mixture of    -   Propylene Glycol Dicaprylate/Dicaprate and Caprylic/Capric        Triglyceride) (Cohort 1)    -   Topical 0.15% of Compound #222 in PEG400 (Cohort 2)    -   Topical 0.05% of Compound #222 in PEG400 (Cohort 3)

Prior to baseline measurements being taken, areas of involvement weremarked on the facial surface using a standard template, to ensure thatinstruments were repositioned in the same location at each visit. Thebiophysical measurements (Surface Evaluation of Living Skin viaVisioscan) were conducted by a trained technician. Pre-treatment HighResolution Scientifically Matched Photographs were taken.

All subjects were instructed to use the test material once a day, aspart of their daily skin care routine. Immediately following baselineevaluations, the subjects were issued the product with the followinginstructions:

GROUP 1—Compound #222 Topical 0.15% in oil (Cohort 1): The subjects wereinstructed to hold the bottle at an angle such that the roller-ball wasat bottom and apply the roller-ball to the periorbital area, includingthe crow's feet area, 2-3 times, starting from the area under the eye(and above the cheekbone) and moving up towards the outer tip of theeye-brow. After 2-3 rolls, they were able to see wetness on the treatedarea. This procedure was repeated for the other eye.

GROUPS 2 & 3 Compound #222 Topical 0.15% in PEG (Cohort 2) & Compound#222 Topical 0.05% in PEG (Cohort 3): The subjects were instructed tohold the dispenser upright with one hand and with the tip of the indexfinger on the pump (similar to holding a spray container), pour a smallamount of the product into the palm of their other hand by pumping onceor twice. The product was then applied on to the periorbital area,including the crow's feet area, of both eyes with their index finger.

After 2, 4, 8 and 12 weeks of daily use of the test products, the testsubjects returned to the study site with the test product applied. Afteracclimating to ambient conditions, High Resolution ScientificallyMatched Photographs were be taken and biophysical measurements (SurfaceEvaluation of Living Skin via Visioscan) were repeated using thestandard template to identify test sites on the face. In addition(during the acclimation period) all participants were be asked to fillout a self-assessment questionnaire.

Surface Evaluation of Living Skin Visioscan: The Visioscan (Courage andKhazaka) took a direct image of the living skin using a measuring headcontaining a CCD-camera and two metal halogen lamps positioned oppositeeach other in order to ensure even illumination of the measuring fieldon the skin (Skin Pharmacol Appl Skin Physiol (1999), 12(1-2), 1-11 andCosmetic & Toiletries magazine (2009), 124(6), 51-54). The grey leveldistribution of the pixels in the image correspond to differentphenomena (white pixels represent desquamation on the skin, dark pixelsrepresent lines and wrinkles). The software with the Visioscanautomatically calculates skin smoothness, skin roughness, scaliness andwrinkle parameters. Visioscan images were taken at the following timepoints: Baseline Day 0 (beginning of the study), Week 2, Week 4, Week 8,and Week 12 (end of the test).

High Resolution Scientifically Matched Photography with PhotoGrammetrix™Image Analysis: Exclusively detailed, high resolution before and afterdigital photographs are taken, with fixed camera background, angles,settings, lighting, panelist positioning, color bars, white balance,standardized and digitally certified unretouched. Each stage in theprogression of the product treatment was photographically documented.This set of photographs provided a visual record of the efficacy of theproducts. Full face, frontal, left 45° and right 45° view photographswere taken at the following time points: Baseline Day 0 (beginning ofthe study), Week 2, Week 4, Week 8, and Week 12 (end of the test).

The source data was Visioscan and PhotoGrammetrix Image Analysisreadings along with subjective assessments, which were totaled andreported as average scores. Photographs were placed side by side as tocompare the photographs of before and after application of the testproduct in the eye area. Wrinkle reduction analysis source dataconsisted of crow's feet area quantification in relative units (px),collected at baseline and, the week 2, 4, 8 and 12 evaluations. The dataobtained via Visioscan and from PhotoGrammetrix Image Analysis wasquoted as % differences from baseline at each of the previouslydescribed time points. A paired t-test analysis was conducted in orderto compare the results of post test product application measurements tobaseline measurements where applicable. Statistical significance wasestablished if p≤(α=0.05) was calculated.

TABLE 2 Self-assessment questionnaire - Compound #222 Topical 0.15% inOil (Cohort 1) 1. My wrinkles in the eye area have improved since thebeginning of the study. Q1 Answer: Strongly Neither agree Strongly agreeAgree or disagree Disagree disagree Score: 1 2 3 4 5 Panelist ID Nos.:Day 7 Day 14 Subject #1 5 4 Subject #2 2 2 Average Score: 3.50 3.00Score vs. % 1 0% 0% Responders: 2 50%  50%  3 0% 0% 4 0% 50%  5 50%  0%2. Compared to the beginning of the study, the appearance of my skinaround either of my eyes is . . . Q2 Answer: Better Little better SameLittle worse Worse Score: 1 2 3 4 5 Panelist ID Nos.: Day 7 Day 14Subject #1 3 3 Subject #2 2 2 Average Score: 2.50 2.50 Score vs. % 1 0%0% Responders: 2 50%  50%  3 50%  50%  4 0% 0% 5 0% 0% 3. Compared tothe beginning of the study, how do you feel about the treated areasurrounding your eyes and the appearance of wrinkles? Q3 Answer: VeryNeither satisfied Very Satisfied Satisfied or dissatisfied DissatisfiedDissatisfied Score: 1 2 3 4 5 Panelist ID Nos.: Day 7 Day 14 Subject #13 3 Subject #2 2 1 Average Score: 2.50 2.00 Score vs. % 1 0% 50% Responders: 2 50%  0% 3 50%  50%  4 0% 0% 5 0% 0% 4. Compared to thebeginning of the study, have you felt any discomfort, other than slighttingling, in the treated area during the study? Q4 Answer: Yes,occasional Yes, occasional Yes, every day Yes, everyday discomfortlasting discomfort lasting lasting less lasting more No less than anhour more than one hour than an hour than an hour Score: 1 2 3 4 5Panelist ID Nos.: Day 7 Day 14 Subject #1 1 1 Subject #2 2 2 AverageScore: 1.50 1.50 Score vs. % 1 50%  50%  Responders: 2 50%  50%  3 0% 0%4 0% 0% 5 0% 0%

TABLE 3 Self-assessment questionnaire - Compound #222 Topical 0.15% inPEG (Cohort 2) 1. My wrinkles in the eye area have improved since thebeginning of the study. Q1 Answer: Strongly Neither agree Strongly agreeAgree or disagree Disagree disagree Score: 1 2 3 4 5 Panelist ID Nos.:Day 7 Day 14 Subject #3 3 2 Subject #4 4 4 Average Score: 3.50 3.00Score vs. % 1 0% 0% Responders: 2 0% 50%  3 50%  0% 4 50%  50%  5 0% 0%2. Compared to the beginning of the study, the appearance of my skinaround either of my eyes is . . . Q2 Answer: Better Little better SameLittle worse Worse Score: 1 2 3 4 5 Panelist ID Nos.: Day 7 Day 14Subject #3 2 2 Subject #4 3 3 Average Score: 2.50 2.50 Score vs. % 1 0%0% Responders: 2 50%  50%  3 50%  50%  4 0% 0% 5 0% 0% 3. Compared tothe beginning of the study, how do you feel about the treated areasurrounding your eyes and the appearance of wrinkles? Q3 Answer: VeryNeither satisfied Very Satisfied Satisfied or dissatisfied DissatisfiedDissatisfied Score: 1 2 3 4 5 Panelist ID Nos.: Day 7 Day 14 Subject #32 2 Subject #4 3 4 Average Score: 2.50 3.00 Score vs. % 1 0% 0%Responders: 2 50%  50%  3 50%  0% 4 0% 50%  5 0% 0% 4. Compared to thebeginning of the study, have you felt any discomfort, other than slighttingling, in the treated area during the study? Q4 Answer: Yes,occasional Yes, occasional Yes, every day Yes, everyday discomfortlasting discomfort lasting lasting less lasting more No less than anhour more than one hour than an hour than an hour Score: 1 2 3 4 5Panelist ID Nos.: Day 7 Day 14 Subject #3 2 4 Subject #4 1 1 AverageScore: 1.50 2.50 Score vs. % 1 50%  50%  Responders: 2 50%  0% 3 0% 0% 40% 50%  5 0% 0%

TABLE 4 Self-assessment questionnaire - Compound #222 Topical 0.05% inPEG (Cohort 3) 1. My wrinkles in the eye area have improved since thebeginning of the study. Q1 Answer: Strongly Neither agree Strongly agreeAgree or disagree Disagree disagree Score: 1 2 3 4 5 Panelist ID Nos.:Day 7 Day 14 Subject #5 2 1 Subject #6 2 2 Average Score: 2.00 1.50Score vs. % 1 0% 50%  Responders: 2 100%  50%  3 0% 0% 4 0% 0% 5 0% 0%2. Compared to the beginning of the study, the appearance of my skinaround either of my eyes is . . . Q2 Answer: Better Little better SameLittle worse Worse Score: 1 2 3 4 5 Panelist ID Nos.: Day 7 Day 14Subject #5 1 1 Subject #6 2 2 Average Score: 1.50 1.50 Score vs. % 150%  50%  Responders: 2 50%  50%  3 0% 0% 4 0% 0% 5 0% 0% 3. Compared tothe beginning of the study, how do you feel about the treated areasurrounding your eyes and the appearance of wrinkles? Q3 Answer: VeryNeither satisfied Very Satisfied Satisfied or dissatisfied DissatisfiedDissatisfied Score: 1 2 3 4 5 Panelist ID Nos.: Day 7 Day 14 Subject #51 1 Subject #6 3 2 Average Score: 2.00 1.50 Score vs. % 1 50%  50% Responders: 2 0% 50%  3 50%  0% 4 0% 0% 5 0% 0% 4. Compared to thebeginning of the study, have you felt any discomfort, other than slighttingling, in the treated area during the study? Q4 Answer: Yes,occasional Yes, occasional Yes, every day Yes, everyday discomfortlasting discomfort lasting lasting less lasting more No less than anhour more than one hour than an hour than an hour Score: 1 2 3 4 5Panelist ID Nos.: Day 7 Day 14 Subject #5 1 1 Subject #6 1 1 AverageScore: 1.00 1.00 Score vs. % 1 100%  100%  Responders: 2 0% 0% 3 0% 0% 40% 0% 5 0% 0%

TABLE 5 Roughness reduction [SEr] via Visioscan - Compound #222 Topical0.15% in Oil (Cohort 1) Panelist Base- Individual % Individual % ID No.:line Day 7 Difference Day 14 Difference Subject #1 2.50 2.46 −1.60% 2.25−9.82% Subject #2 1.90 1.48 −21.90% 1.29 −31.93% Mean: 2.20 1.97 1.77 %Difference −10.36% −19.36%

TABLE 6 Roughness reduction [SEr] via Visioscan - Compound #222 Topical0.15% in PEG (Cohort 2) Panelist Base- Individual % Individual % ID No.:line Day 7 Difference Day 14 Difference Subject #3 2.21 1.95 −11.79%1.90 −13.83% Subject #4 1.51 1.39 −7.84% 1.35 −10.63% Mean: 1.86 1.671.62 % Difference −10.19% −12.53%

TABLE 7 Roughness reduction [SEr] via Visioscan - Compound #222 Topical0.05% in PEG (Cohort 3) Panelist Base- Individual % Individual % ID No.:line Day 7 Difference Day 14 Difference Subject #5 2.58 1.83 −29.07%1.77 −31.40% Subject #6 1.52 1.44 −5.26% 1.24 −18.42% Mean: 2.05 1.641.51 % Difference −20.24% −26.59%

Example 2

Four groups of women were recruited to evaluate and compare the efficacyof four anti-aging test products (targeting the periorbital eye area)intended to reduce the appearance of fine lines, wrinkles in the outercanthus of the eyes (crow's feet area) over a 12 week period. Wrinkleassessment was conducted instrumentally using a Visioscan image analysissystem. Effectiveness of the test product was evaluated using panelistself-assessment via questionnaire responses. Each stage in theprogression of treatments was photographically documented using HighResolution Scientifically Matched Photography technique. Image analysiswas utilized to quantify changes in fine lines and crow's feet conditionobserved in the Scientifically Matched Photographs.

Subject Selection:

-   -   Number: Eighty three subjects (twenty or twenty one per group)        to complete the study.    -   Sex: Females    -   Race: Caucasian/Asian/Hispanic    -   Age Range: 40 through 60 years old

Test samples:

-   -   Topical 0.15% of Compound #222 in Oil (a 50/50 mixture of        Propylene Glycol Dicaprylate/Dicaprate and Caprylic/Capric        Triglyceride) (Cohort 1)    -   Topical 0.05% of Compound #222 in Oil (a 50/50 mixture of        Propylene Glycol Dicaprylate/Dicaprate and Caprylic/Capric        Triglyceride) (Cohort 2)    -   Topical 0.15% of Compound #222 in PEG400 (Cohort 3)    -   Topical 0.05% of Compound #222 in PEG400 (Cohort 4)

The testing protocol and evaluation was the same as in Example 1.

FIGS. 1 and 2 show the average change in roughness from baseline andpercent wrinkle reduction of test subjects skin after topical treatmentof the periorbital areas by compound #222 in all 4 cohorts.

Table 8 below shows more detail of Cohort 1 at week 8 and week 12 ascompared to baseline.

TABLE 8 Change in Roughness and Change in Wrinkle Depth via Visioscan -Compound #222 Topical 0.05% in Oil (Cohort 2) at week 8 and week 12.Week 8 Week 12 Number of 21 21 test subjects Change in Roughness Mean(SD) −0.85 (0.59) −1.01 (0.59) Median −0.67 [−2.00, −0.02] −0.79 [−1.79,−0.21] [Min, Max] % Change in Roughness Mean (SD) −32.9% (15.8) −39.3%(14.6) Median −33.9% [−57.7, −0.9] −40.9% [−59.8, −10.3] [Min, Max]Change in Wrinkle Depth (×10⁴) Mean (SD) −0.89 (0.63) −0.92 (0.76)Median −0.79 [−2.10, 0.05] −0.85 [−2.47, 0.49] [Min, Max] % Change inWrinkle Depth Mean (SD) −58.0% (24.2) −54.1% (35.5) Median −59.3%[−86.8, 4.1] −63.5% [−88.2, 38.9] [Min, Max]

What is claimed is:
 1. A method for improving the aesthetic appearanceof a subject's skin, the method comprising administering to the subjectan effective amount of a compound which is

or a dermatologically acceptable salt thereof.
 2. A method for improvingthe aesthetic appearance of a subject's skin, the method comprisingadministering to the skin an effective amount of a cosmetic ordermopharmaceutical composition comprising a compound which is

or a dermatologically acceptable salt thereof, and a dermatologicallyacceptable excipient.
 3. The method of claim 1, wherein the improvementin aesthetic appearance is improvement in one or more of skin tone,radiance, clarity, tautness, skin firmness, plumpness, suppleness,softness, skin texture, skin texturization and moisturization,appearance of skin contours, appearance of hollow cheeks, appearance ofsunken, baggy, or dark circles under eyes, skin luster, brightness, skinthickness, and skin elasticity and/or resiliency.
 4. The method of claim1, wherein the improvement in aesthetic appearance is the reduction offine lines or wrinkles.
 5. The method of claim 1, wherein theimprovement in aesthetic appearance is the improvement in procollagenand/or collagen production.
 6. The method of claim 1, wherein theimprovement in aesthetic appearance is the reduction of discoloration ofskin.
 7. The method of claim 2, wherein the cosmetic ordermopharmaceutical composition is a topical composition.
 8. The methodof claim 2, wherein the cosmetic composition is intended for use as anon-therapeutic treatment.
 9. A method for improving the aestheticappearance of a subject's skin, the method comprising administering tothe subject an effective amount of a compound which is

or a dermatologically acceptable salt thereof.
 10. A method forimproving the aesthetic appearance of a subject's skin, the methodcomprising administering to the skin an effective amount of a cosmeticor dermopharmaceutical composition comprising a compound which is

or a dermatologically acceptable salt thereof, and a dermatologicallyacceptable excipient.
 11. The method of claim 9, wherein the improvementin aesthetic appearance is improvement in one or more of skin tone,radiance, clarity, tautness, skin firmness, plumpness, suppleness,softness, skin texture, skin texturization and moisturization,appearance of skin contours, appearance of hollow cheeks, appearance ofsunken, baggy, or dark circles under eyes, skin luster, brightness, skinthickness, and skin elasticity and/or resiliency.
 12. The method ofclaim 9, wherein the improvement in aesthetic appearance is thereduction of fine lines or wrinkles.
 13. The method of claim 9, whereinthe improvement in aesthetic appearance is the improvement inprocollagen and/or collagen production.
 14. The method of claim 9,wherein the improvement in aesthetic appearance is the reduction ofdiscoloration of skin.
 15. The method of claim 10, wherein the cosmeticor dermopharmaceutical composition is a topical composition.
 16. Themethod of claim 10, wherein the cosmetic composition is intended for useas a non-therapeutic treatment.